US7884094B2 - Compounds for the treatment of proliferative disorders - Google Patents

Compounds for the treatment of proliferative disorders Download PDF

Info

Publication number
US7884094B2
US7884094B2 US11/355,922 US35592206A US7884094B2 US 7884094 B2 US7884094 B2 US 7884094B2 US 35592206 A US35592206 A US 35592206A US 7884094 B2 US7884094 B2 US 7884094B2
Authority
US
United States
Prior art keywords
phenyl
optionally substituted
isoxazole
methoxy
trimethoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related, expires
Application number
US11/355,922
Other languages
English (en)
Other versions
US20060217389A1 (en
Inventor
Lijun Sun
Christopher Borella
Hao Li
Jun Jiang
Shoujun Chen
Keizo Koya
Takayo Inoue
Zhenjian Du
Kevin Foley
Yaming Wu
Mei Zhang
Weiwen Ying
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synta Phamaceuticals Corp
Original Assignee
Synta Phamaceuticals Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synta Phamaceuticals Corp filed Critical Synta Phamaceuticals Corp
Priority to US11/355,922 priority Critical patent/US7884094B2/en
Assigned to SYNTA PHARMACEUTICALS CORP. reassignment SYNTA PHARMACEUTICALS CORP. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BORELLA, CHRISTOPHER, DU, ZHENJIAN, SUN, LIJUN, JIANG, JUN, ZHANG, MEI, CHEN, SHOUJUN, FOLEY, KEVIN, INOUE, TAKAYO, KOYA, KEIZO, LI, HAO, WU, YAMING, YING, WEIWEN
Publication of US20060217389A1 publication Critical patent/US20060217389A1/en
Priority to US12/883,883 priority patent/US8269017B2/en
Application granted granted Critical
Publication of US7884094B2 publication Critical patent/US7884094B2/en
Priority to US13/558,886 priority patent/US8598366B2/en
Priority to US14/053,845 priority patent/US9090603B2/en
Expired - Fee Related legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings

Definitions

  • chemotherapeutic methods are now available to be used in the treatment of cancer.
  • One of the most successful methods is the use of anti-mitotic agents which interfere with the assembly or disassembly of microtubules. Since microtubule assemble and disassemble is necessary for mitosis, inhibition of either the assembly or disassembly of microtubules interferes with cell proliferation.
  • compounds that inhibit the assembly of microtubule are useful in treating diseases or conditions which are caused or exasperated by rapid or abnormal cell proliferation, such as cancer.
  • vinca alkaloids which inhibit microtubule assembly have proved clinically successful: Vincristine has been successfully used to treat hematological malignancies and non-small-cell lung carcinoma; Vinblastine has been successfully used to treat hematological malignancies, testicular carcinomas and non-small-cell lung carcinoma; and Vinorelbine has been successfully used to treat hematological malignancies, breast carcinomas and non-small-cell lung carcinoma.
  • taxanes which inhibit microtubule disassemble have also proved to be clinically successful.
  • Paclitaxel has been successful in treating breast, ovarian and non-small-cell lung carcinomas; and Docetaxel has been successful in treating breast and non-small-cell lung carcinomas.
  • the invention relates to compounds of formula (I):
  • R a or R b is —H and the other is an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R 2 is an optionally substituted phenyl, an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted biphenyl, an optionally substituted 4-pyridinyl-phenyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted 1H-indolyl, an optionally substituted pyridinyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted thiazolyl, an optionally substituted isothiazolyl, an optionally substituted imidazolyl, an optionally substituted pyrrolyl, an optionally substituted pyrazolyl, an optionally substituted furanyl, an optionally substituted thiophenyl, an optionally substituted thiadiazolyl, an optionally substituted o
  • R c or R d is —H and the other is an optionally substituted heteroaryl, an unsubstituted phenyl, or a substituted phenyl represented by one of the following formulas:
  • R 21 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7
  • R 7 and R 8 are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R 10 and R 11 are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R 17 for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
  • p 1 or 2.
  • Compounds of the invention or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof are potent antimitotic agents which inhibiting tubulin polymerization, and thus can inhibit microtubule growth.
  • microtubules In order for cells to undergo mitosis, microtubules must be able to assemble and disassemble, in a process known as dynamic instability.
  • the compounds of the invention can be used to inhibit tubulin polymerization in a cell by contacting the cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • compounds of the invention can be used to inhibit tubulin polymerization in a subject by administering to the subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • Compounds of the invention or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof are vascular targeting agents which can be used to block, occlude, or otherwise disrupt blood flow in neovasculature, and thus lead to destruction of vasculature.
  • compounds of the invention can be used to block, occlude, or otherwise disrupt blood flow in neovasculature by contacting the neovasculature with an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • All of the methods of this invention may be practice with a compound of the invention alone, or in combination with other agents, such as other anti-cancer agents.
  • compounds of the invention overcome or ameliorated some of the limitation of known anti-mitotic agents.
  • compounds of the invention are cytotoxic in multidrug resistant cells, and thus may be useful for treating cancers that have become resistant to other therapies.
  • FIG. 1 shows the cytotoxic effects of compounds of the invention on hepatocytes compared to untreated cells and to known cancer drugs Taxol and 17AAG.
  • FIG. 2 shows the cytotoxic effects of compounds of the invention on hepatocytes compared to untreated cells and to known cancer drug 17AAG.
  • FIG. 3 shows the microtubule network of Chinese Hamster Ovary (CHO) cells transfected with a vector encoding ⁇ -tubulin-YFP after they have been treated with DMSO.
  • FIG. 4 shows the microtubule network of CHO cells transfected with a vector encoding ⁇ -tubulin-YFP after they have been treated with 0.1 ⁇ M Taxol.
  • FIG. 5 shows the microtubule network of CHO cells transfected with a vector encoding ⁇ -tubulin-YFP after they have been treated with 0.1 ⁇ M Compound 1.
  • FIG. 6 shows the microtubule network of CHO cells transfected with a vector encoding ⁇ -tubulin-YFP after they have been treated with 0.1 ⁇ M Compound 3.
  • FIG. 7 shows the microtubule network of CHO cells transfected with a vector encoding ⁇ -tubulin-YFP after they have been treated with 0.1 ⁇ M Compound 6.
  • FIG. 8C shows the microtubule network of CV-1 cells 24 hrs after treatment with colchicine.
  • FIG. 8D shows the microtubule network of CV-1 cells 24 hrs after treatment with vincristine.
  • FIG. 8E shows a magnified view of the microtubule network of CV-1 cells 24 hrs after treatment with Compound 3.
  • FIG. 9A shows the microtubule network of CV-1 cells 48 hrs after treatment with DMSO.
  • FIG. 9B shows the microtubule network of CV-1 cells 48 hrs after treatment with Compound 3.
  • FIG. 9C shows the microtubule network of CV-1 cells 48 hrs after treatment with colchicine.
  • FIG. 9E shows a magnified view of the microtubule network of CV-1 cells 48 hrs after treatment with Compound 3.
  • FIG. 10B shows the microtubule network of CV-1 cells 72 hrs after treatment with Compound 3.
  • FIG. 10C shows the microtubule network of CV-1 cells 72 hrs after treatment with colchicine.
  • FIG. 10D shows the microtubule network of CV-1 cells 72 hrs after treatment with vincristine.
  • FIG. 11 shows the results of a nude mouse xenograft study to determine the effect of Compound 3 on the in vivo growth rate of the human tumor cell line MDA-MB435S.
  • Tumor bearing animals (10 mice/group) were i.v. injected 3 times per week for a total of 10 doses (hatched bar) and the average tumor volumes for each group ( ⁇ SEM) were determined every 2-4 days.
  • Treatment with doses of 12.5 and 25 mg/kg body weight of Compound 3 caused tumor regression, whereas a dose of 7.5 mg/kg body weight of paclitaxel did not.
  • FIG. 12 shows percent change in body weight of animals during the study presented in FIG. 11 .
  • Treatment with Compound 3 did not cause overt toxicity in a nude mouse xenograft model using the human tumor cell line MDA-MB-435S.
  • Tumor bearing animals (10 mice/group) were i.v. injected 3 times per week for a total of 10 doses (hatched bar) and the cumulative average percent changes in body weights for each group relative to the start of dosing (+/ ⁇ SEM) were determined every 1-3 days.
  • Treatment with doses of 6.25, 12.5 and 25 mg/kg body weight of Compound 3 was not overtly toxic, as indicated by the minimal effects on the animal body weights in the test article-treated versus vehicle-treated groups.
  • FIG. 15 shows the results of a nude mouse xenograft study to determine the effects of Compounds 169 and 174 on the in vivo growth rate of the human tumor cell line MDA-MB-435S.
  • Tumor bearing animals (8 mice/group) were i.v. injected 1 time per week for a total of 3 doses (arrowheads) and the median tumor volumes for each group (error bars represent SEM) were determined every 3-4 days.
  • Treatment with doses of 2 mg/kg body weight of Compound 169 and 4.55 mg/kg body weight of Compound 174 substantially inhibited tumor growth.
  • FIG. 16 shows percent change in body weight of animals during the study presented in FIG. 15 .
  • Treatment with Compounds 169 and 174 did not cause overt toxicity in a nude mouse xenograft model using the human tumor cell line MDA-MB-435S (data derived from the same study presented in FIG. 15 ).
  • Tumor bearing animals (8 mice/group) were i.v. injected 1 time per week for a total of 3 doses (arrowheads) and the cumulative average percent changes in body weights for each group relative to the start of dosing were determined every 1-4 days (error bars not shown for clarity).
  • FIG. 17 shows the results of a nude mouse xenograft study to determine the effect of Compound 178 on the in vivo growth rate of the human tumor cell line MDA-MB-435S.
  • Tumor bearing animals (8 mice/group) were i.v. injected with Compound 178 3 times per week for a total of 3 doses at 25 mg/kg body weight (closed arrowheads), followed by 3 times per week for a total of 3 doses at 37.5 mg/kg body weight (open arrowheads), followed by 3 times per week for a total of 3 doses at 50 mg/kg body weight (arrows).
  • the median tumor volumes for each group (error bars represent SEM) were determined every 3-5 days.
  • Compound 178 began to show moderate efficacy at doses of 37.5 and 50 mg/kg body weight.
  • FIG. 19 shows the effect of Compound 3 on the in vivo induction of tumor necrosis in an EMT6 mouse mammary carcinoma tumor model in nude mice.
  • Tumor-bearing animals (5 mice/group) were given a single i.v. bolus injection of either vehicle or Compound 3, and at the indicated time points following dosing the tumors were excised and processed for histology.
  • Light microscopy was used to quantitate the average area of necrosis as a percent of total area in tumor sections from each treatment group (error bars represent SEM).
  • Treatment with a single dose of 25 mg/kg body weight of Compound 3 resulted in a near maximal 2.4 fold increase in tumor necrosis at 4 hours following drug treatment.
  • FIG. 20A shows the microtubule network of CV-1 cells 24 hrs after treatment with DMSO.
  • FIG. 20B shows the microtubule network of CV-1 cells 24 hrs after treatment with 1 nM of Compound 249.
  • FIG. 20C shows the microtubule network of CV-1 cells 24 hrs after treatment with 10 nM of Compound 249.
  • FIG. 20E shows the microtubule network of CV-1 cells 24 hrs after treatment with 1000 nM of Compound 249.
  • FIG. 21A shows the microtubule network of HUVEC cells 24 hrs after treatment with DMSO.
  • FIG. 21B shows the microtubule network of HUVEC cells 24 hrs after treatment with 1 nM of Compound 249.
  • FIG. 21C shows the microtubule network of HUVEC cells 24 hrs after treatment with 5 nM of Compound 249.
  • FIG. 21D shows the microtubule network of HUVEC cells 24 hrs after treatment with 10 nM of Compound 249.
  • FIG. 21E shows the microtubule network of HUVEC cells 24 hrs after treatment with 50 nM of Compound 249.
  • FIG. 22 shows a nude mouse tumor study to determine the effect of Compound 174 on the in vivo growth rate of the allogeneic mouse mammary carcinoma cell line EMT6.
  • Tumor-bearing animals (15 mice/group) were given a single i.v. bolus injection of either vehicle or Compound 174, and changes in median tumor volumes (error bars represent SEM) for each group were determined after 3 days.
  • Treatment with doses of 4.55 and 3.22 mg/kg body weight of Compound 174 substantially inhibited tumor growth.
  • the largest average percent change in body weight observed for any group in this study was ⁇ 7.3% (+/ ⁇ 0.9 SEM) one day after dosing Compound 174 at 4.55 mg/kg body weight. No individual animal lost >11% body weight at any point over the course of the study.
  • an “aromatic ring” or “aryl” means a monocyclic or polycyclic-aromatic ring or ring radical comprising carbon and hydrogen atoms.
  • aryl groups typically have about 6 to about 14 carbon atom ring members.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • An aryl group can be unsubstituted or substituted with one or more substituents (including without limitation alkyl (preferably, lower alkyl or alkyl substituted with one or more halo), hydroxy, alkoxy (preferably, lower alkoxy), alkylsulfanyl, cyano, halo, amino, and nitro.
  • the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms.
  • alkyl means a saturated straight chain or branched non-cyclic hydrocarbon typically having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl,
  • any carbon in the alkyl segment may be substituted with oxygen ( ⁇ O), sulfur ( ⁇ S), or nitrogen ( ⁇ NR 32 , wherein R 32 is —H, an alkyl, acetyl, or aralkyl). Lower alkyls are typically preferred for the compounds of this invention.
  • alkylene refers to an alkyl group or a cycloalkyl group that has two points of attachment to two moieties (e.g., ⁇ —CH 2 — ⁇ , — ⁇ CH 2 CH 2 — ⁇ ,
  • Alkylene groups may be optionally substituted with one or more substituents.
  • alkylsulfanyl refers to an alkyl group which is linked to another moiety though a divalent sulfur atom. Alkylsulfanyl groups can be optionally substituted with one or more substituents.
  • arylsulfanyl refers to an aryl group which is linked to another moiety though a divalent sulfur atom.
  • Arylsulfanyl groups can be optionally substituted with one or more substituents.
  • alkyl ester refers to a group represented by the formula —C(O)OR 32 , wherein R 32 is an alkyl group.
  • a lower alkyl ester is a group represented by the formula —C(O)OR 32 , wherein R 32 is a lower alkyl group.
  • heteroalkyl refers to an alkyl group which has one or more carbons in the alkyl chain replaced with an —O—, —S— or —NR 33 —, wherein R 33 is H or a lower alkyl. Heteroalkyl groups can be optionally substituted with one or more substituents.
  • alkylamino refers to an amino group in which one hydrogen atom attached to the nitrogen has been replaced by an alkyl group.
  • dialkylamino refers to an amino group in which two hydrogen atoms attached to the nitrogen have been replaced by alkyl groups, in which the alkyl groups can be the same or different. Alkylamino groups and dialkylamino groups can be optionally substituted with one or more substituents.
  • alkenyl means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond.
  • Representative straight chain and branched alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl and the like.
  • Alkenyl groups can be optionally substituted with one or more substituent
  • alkynyl means a straight chain or branched, hydrocarbon radical typically having from 2 to 10 carbon atoms and having at lease one carbon-carbon triple bond.
  • Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,-1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl and the like.
  • cycloalkyl means a saturated, mono- or polycyclic alkyl radical typically having from 3 to 14 carbon atoms.
  • Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantly, decahydronaphthyl, octahydropentalene, bicycle[1.1.1]pentanyl, and the like. Cycloalkyl groups can be optionally substituted with one or more substituents.
  • cycloalkenyl means a cyclic non-aromatic alkenyl radical having at least one carbon-carbon double bond in the cyclic system and typically having from 5 to 14 carbon atoms.
  • Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl and the like. Cycloalkenyl groups can be optionally substituted with one or more substituents.
  • heterocycle or “heterocyclyl” means a monocyclic or polycyclic heterocyclic ring (typically having 3- to 14-members) which is either a saturated ring or an unsaturated non-aromatic ring.
  • a 3-membered heterocycle can contain from 1 to 3 heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 to about 8 heteroatoms.
  • Each heteroatom is independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 4H-pyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • a heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group.
  • the heterocyclyl may be optionally substituted with one or more substituents (including without limitation a halo, an alkyl, a haloalkyl, or aryl). Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.
  • heteroaromatic or “heteroaryl” means a monocyclic or polycyclic heteroaromatic ring (or radical thereof) comprising carbon atom ring members and one or more heteroatom ring members (such as, for example, oxygen, sulfur or nitrogen).
  • the heteroaromatic ring has from 5 to about 14 ring members in which at least 1 ring member is, a heteroatom selected from oxygen, sulfur and nitrogen.
  • the heteroaromatic ring is a 5 or 6 membered ring and may contain from 1 to about 4 heteroatoms.
  • the heteroaromatic ring system has a 7 to 14 ring members and may contain from 1 to about 7 heteroatoms.
  • heteroaryls include pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoquniolyl, indazolyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, benzo[1,3]d ioxolyl, 2,3-dihyd ro-benzo[1,4]dioxinyl, benzimidazolyl, benzoxazolyl,
  • halogen or “halo” means —F, —Cl, —Br or —I.
  • haloalkyl means an alkyl group in which one or more —H is replaced with a halo group.
  • haloalkyl groups include —CF 3 , —CHF 2 , —CCl 3 , —CH 2 CH 2 Br, —CH 2 CH(CH 2 CH 2 Br)CH 3 , —CHICH 3 , and the like.
  • haloalkoxy means an alkoxy group in which one or more —H is replaced with a halo group.
  • haloalkoxy groups include —OCF 3 and —OCHF 2 .
  • Bioisostere and “bioisosteric replacement” have the same meanings as those generally recognized in the art.
  • Bioisosteres are atoms, ions, or molecules in which the peripheral layers of electrons can be considered substantially identical.
  • the term bioisostere is usually used to mean a portion of an overall molecule, as opposed to the entire molecule itself.
  • Bioisosteric replacement involves using one bioisostere to replace another with the expectation of maintaining or slightly modifying the biological activity of the first bioisostere.
  • the bioisosteres in this case are thus atoms or groups of atoms having similar size, shape and electron density.
  • Preferred bioisosteres of esters, amides or carboxylic acids are compounds containing two sites for hydrogen bond acceptance.
  • the ester, amide or carboxylic acid bioisostere is a 5-membered monocyclic heteroaryl ring, such as an optionally substituted 1H-imidazolyl, an optionally substituted oxazolyl, 1H-tetrazolyl, [1,2,4]triazolyl, or an optionally substituted [1,2,4]oxadiazolyl.
  • the terms “subject”, “patient” and “animal”, are used interchangeably and include, but are not limited to, a cow, monkey, horse, sheep, pig, mini pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig and human.
  • the preferred subject, patient or animal is a human.
  • lower refers to a group having up to four carbon atoms.
  • a “lower alkyl” refers to an alkyl radical having from 1 to 4 carbon atoms
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
  • a lower alkoxy or a lower alkylsulfanyl refers to an alkoxy or an alkylsulfanyl having from 1 to 4 carbon atoms. Lower substituents are typically preferred.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • Suitable substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include any substituent which will form a stable compound of the invention.
  • substituents for an alkyl, alkoxy, alkylsulfanyl, alkylamino, dialkylamino, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl include an alkyl, an alkoxy, an alkylsulfanyl, an alkylamino, a dialkylamino, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, a haloalkyl, —C(O)NR 34 R 35 , —NR 36 C(O)R 37 , halo, —OR 36 , cyano, nitro, haloalkoxy, —C(O
  • alkyl, cycloalkyl, alkylene, a heterocyclyl, and any saturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, and heteroaralkyl groups may also be substituted with ⁇ O, ⁇ S, ⁇ N—R 32 .
  • heterocyclyl, heteroaryl, or heteroaralkyl group When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). Typically, such compounds are stable at a temperature of 40° C. or less, in the absence of excessive moisture, for at least one week. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
  • amino acid residue refers to what is left of an amino acid (losing a H+from the nitrogenous side, an OH ⁇ from the carboxylic side, or a H + from the nitrogenous side and an OH ⁇ from the carboxylic side) in the formation of a peptide bond(s).
  • An “amino acid analog” includes D or L amino acids having the following formula: NH 2 —CHR—C(O)OH, wherein R is an optionally substituted alkyl group, an optionally substituted heteroalkyl group, an optionally substituted aromatic group, or an optionally substituted heteroaromatic group, and wherein R does not correspond to the side chain of a naturally-occurring amino acid.
  • amino acid residue analog refers to what is left of an amino acid analog (losing a H + from the nitrogenous side, an OH ⁇ from the carboxylic side, or a H + from the nitrogenous side and an OH ⁇ from the carboxylic side) in the formation of a peptide bond(s).
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, but they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • prodrugs include derivatives of compounds of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1 that comprise —NO, —NO 2 , —ONO, or —ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by 1 B URGER'S M EDICINAL C HEMISTRY AND D RUG D ISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5 th ed), the entire teachings of which are incorporated herein by reference.
  • the term “pharmaceutically acceptable salt,” is a salt formed from an acid and a basic group of one of the compounds of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., 1,1′-methylene-bis-(
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1 having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxy
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1 having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,and p-toluenesulfonic acid.
  • clathrate means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • spaces e.g., channels
  • guest molecule e.g., a solvent or water
  • Inhibition of tubulin polymerization can be determined by any method known to those skilled in the art, such as the method described herein in Example 7.
  • the amount of a tubulin polymerization inhibitor that inhibits 50% of tubulin polymerization that occurs in the absence of the inhibitor i.e., the IC 50
  • the amount of a tubulin polymerization inhibitor that inhibits 50% of tubulin polymerization that occurs in the absence of the inhibitor i.e., the IC 50
  • the amount of a tubulin polymerization inhibitor that inhibits 50% of tubulin polymerization that occurs in the absence of the inhibitor i.e., the IC 50
  • the IC 50 can be determined by pre-incubating purified tubulin with various amounts of an inhibitor for 15 minutes at 37° C. The mixture is then cooled to room temperature and GTP is added to induce tubulin polymerization. The polymerization can be monitored in a spectrophotometer at 350 nm.
  • a “proliferative disorder” or a “hyperproliferative disorder,” and other equivalent terms, means a disease or medical condition involving pathological growth of cells.
  • Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy (e.g., diabetic retinopathy or other retinopathies), choroidal neovascularisation (e.g., macular degeneration), cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, and desmoid tumors.
  • Smooth muscle cell proliferation includes hyperproliferation of cells in the vasculature, for example, intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly stenosis following biologically- or mechanically-mediated vascular injury, e.g., vascular injury associated with angioplasty.
  • intimal smooth muscle cell hyperplasia can include hyperplasia in smooth muscle other than the vasculature, e.g., bile duct blockage, bronchial airways of the lung in patients with asthma, in the kidneys of patients with renal interstitial fibrosis, and the like.
  • Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.
  • the proliferative disorder is cancer.
  • Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medu
  • leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC-1 (murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia (e.g., as exemplified by the SB (acute) cell line), and B-lymphocytic leukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia
  • the compounds of the invention are believed to be particularly effective in treating subject with hematological malignancies (e.g., Hodgkin's disease, Non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and multiple myeloma).
  • hematological malignancies e.g., Hodgkin's disease, Non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and multiple myeloma.
  • the compounds of the invention are believed to be particularly useful in treating solid tumors.
  • the compounds of the invention are particularly effective at treating subjects whose cancer has become “multi-drug resistant”.
  • a cancer which initially responded to an anti-cancer drug becomes resistant to the anti-cancer drug when the anti-cancer drug is no longer effective in treating the subject with the cancer.
  • many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug.
  • Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug.
  • Cancers that have developed resistance to two or more anti-cancer drugs are said to be “multi-drug resistant”. For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
  • an “effective amount” is the quantity of compound in which a beneficial outcome is achieved when the compound is administered to a subject or alternatively, the quantity of compound that possess a desired activity in vivo or in vitro.
  • a beneficial clinical outcome includes reduction in the extent or severity of the symptoms associated with the disease or disorder and/or an increase in the longevity and/or quality of life of the subject compared with the absence of the treatment.
  • a “beneficial clinical outcome” includes a reduction in tumor mass, a reduction in the rate of tumor growth, a reduction in metastasis, a reduction in the severity of the symptoms associated with the cancer and/or an increase in the longevity of the subject compared with the absence of the treatment.
  • Effective amounts of the disclosed compounds typically range between about 1 mg/mm 2 per day and about 10 grams/mm 2 per day, and preferably between 10 mg/mm 2 per day and about 1 gram/mm 2 .
  • compounds of the invention are vascular targeting agents.
  • compounds of the invention are effective for blocking, occluding, or otherwise disrupting blood flow in “neovasculature.”
  • the invention provides a novel treatment for diseases involving the growth of new blood vessels (“neovasculature”), including, but not limited to: cancer; infectious diseases; autoimmune disorders; benign tumors, e.g.
  • hemangiomas acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, e.g., diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome, choroidal neovascularization, uvietis and Pterygia (abnormal blood vessel growth) of the eye; rheumatoid arthritis; psoriasis; warts; allergic dermatitis; blistering disease; Karposi sarcoma; delayed wound healing; endometriosis; uterine bleeding; ovarian cysts; ovarian hyperstimulation; vasculogenesis; granulations; hypertrophic scars (keloids); nonunion
  • Vascular targeting can be demonstrated by any method known to those skilled in the art, such as the method described herein in Example 11.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • the chemical structures depicted herein, including the compounds of this invention encompass all of the corresponding compounds' enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric, diastereomeric, and geometric isomeric mixtures.
  • one enantiomer, diastereomer, or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to others. In those cases, such enantiomers, diastereomers, and geometric isomers of a compound of this invention are preferred.
  • composition that “substantially” comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
  • composition that is “substantially free” of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
  • a reaction that is “substantially complete” means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the invention relates to compounds and pharmaceutical compositions that are useful for inhibiting tubulin polymerization and are particularly useful in treating or preventing proliferative disorders, such as cancer.
  • the invention also relates to compounds and pharmaceutical compositions that are useful as vascular targeting agents, particularly, in blocking, occluding, or otherwise disrupting blood flow in neovasculature.
  • the invention relates to compounds of formula (I):
  • R a or R b is —H and the other is an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R 2 is an optionally substituted phenyl, an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted biphenyl, an optionally substituted 4-pyridinyl-phenyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted 1H-indolyl, an optionally substituted pyridinyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted thiazolyl, an optionally substituted isothiazolyl, an optionally substituted imidazolyl, an optionally substituted pyrrolyl, an optionally substituted pyrazolyl, an optionally substituted furanyl, an optionally substituted thiophenyl, an optionally substituted thiadiazolyl, an optionally substituted o
  • the invention relates to compounds of formula (II):
  • R c or R d is —H and the other is an optionally substituted heteroaryl, an unsubstituted phenyl, or a substituted phenyl represented by one of the following formulas:
  • R 4 is an optionally substituted aryl or an optionally substituted heteroaryl
  • R 18 , R 19 , R 22 , and R 23 are each, independently, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 ,
  • R 20 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7 , —S
  • R 21 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7
  • R 7 and R 8 are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R 10 and R 11 are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R 17 for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
  • p 1 or 2.
  • the invention relates to compounds of formula (III):
  • R e or R f is —H and the other is an optionally substituted aryl or an optionally substituted heteroaryl selected from the group consisting of an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted 1H-indolyl, an optionally substituted pyridinyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted thiazolyl, an optionally substituted isothiazolyl, an optionally substituted imidazolyl, an optionally substituted pyrazolyl, an optionally substituted furanyl, an optionally substituted thiophenyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, an optionally substituted
  • R 2 is defined as for formula (I).
  • the invention relates to compounds of formula (IV):
  • R g or R h is —H and the other is:
  • R 4 , R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 are defined as for formula (II).
  • the invention relates to compounds of formula (V):
  • R i or R j is —H and the other is represented by the following formula:
  • X 1 and X 2 are each, independently, CH or N;
  • R 12 , R 13 and R 14 are each, independently, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR
  • R 2 is defined as for formula (I);
  • R 7 , R 8 , R 10 , R 11 , and p are defined as for formula (II).
  • the invention relates to compounds of formula (VI):
  • R k or R l is —H and the other is represented by the following formula:
  • the dashed line indicates that the bond is a single bond or a double bond
  • X 3 and X 4 are each, independently, CH, N, CH 2 , NR 16 , O, or S;
  • X 5 and X 6 are each, independently, CR 29 or N;
  • R 15 is H, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR
  • R 16 is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is an alkyl, a cycloalkyl, or an aralkyl;
  • R 29 for each occurrence, is independently, H or a substituent
  • R 7 , R 8 , R 10 , R 11 , R 17 , and p are defined as for formula (II).
  • the invention relates to compounds of formula (VII):
  • R m or R n is —H and the other is represented by the following formula:
  • R 4 , R 18 , R 19 , and R 20 are defined as for formula (II);
  • X 1 and X 2 are defined as for formula (V).
  • the invention relates to compounds of formula (VIII):
  • R 4 , R 21 , R 22 , and R 23 are defined as for formula (II);
  • X 1 and X 2 are defined as for formula (V).
  • the invention relates to compounds of formula (IX):
  • R q or R r is —H and the other is represented by the following formula:
  • R 4 is defined as for formula (II);and
  • R 15 and R 29 are defined as for formula (VI).
  • the invention relates to compounds of formula (X):
  • R s or R t is —H and the other is represented by the following formula:
  • R 4 is defined as for formula (II);
  • R 15 , R 16 , and R 29 are defined as for formula (VI).
  • the invention relates to compounds of formula (IA):
  • R a or R b is —H and the other is an optionally substituted aryl, or an optionally substituted heteroaryl;
  • R x is (R aa ) m , —R aa —C(O)(CH 2 ) n C(O)OH, —C(O)(CH 2 ) n C(O)OH, —C(O)YR z , —C(O)NH—R aa , or —(R aa ) q C(O)(Y 1 );
  • R y is —H or lower alkyl
  • R w is —H, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl;
  • R 7 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R aa is an amino acid residue or an amino acid residue analog
  • Y is CH 2 , O, or NH
  • R z is Alk-NH 2 , Alk-C(O)OH, Het, or Y 1 ;
  • Alk is an optionally substituted alkylene
  • Het is an optionally substituted heteroalkyl
  • Y 1 is a water soluble polymer with a molecular weight less than 60,000 daltons
  • n 1, 2, 3, or 4;
  • n is an integer from 1 to 10;
  • q 0 or 1.
  • the invention relates to compounds of formula (IIA):
  • R c or R d is —H and the other is an optionally substituted heteroaryl, an unsubstituted phenyl, a substituted phenyl represented by one of the following formulas:
  • R 18 , R 19 , R 22 , and R 23 are each, independently, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 ,
  • R 20 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7 , —S
  • R 21 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7
  • R 10 and R 11 are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R 17 for each occurrence, is independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • p 1 or 2;
  • R x , R y , and R w are defined as for formula (IA).
  • the invention relates to compounds of formula (IIIA):
  • R e or R f is —H and the other is an optionally substituted aryl or an optionally substituted heteroaryl selected from the group consisting of an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted 1H-indolyl, an optionally substituted pyridinyl, an optionally substituted oxazolyl, an optionally substituted isoxazolyl, an optionally substituted thiazolyl, an optionally substituted isothiazolyl, an optionally substituted imidazolyl, an optionally substituted pyrazolyl, an optionally substituted furanyl, an optionally substituted thiophenyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, an optionally substituted
  • the invention relates to compounds of formula (IVA):
  • R g or R h is —H and the other is:
  • R 7 and R 8 are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R 10 and R 11 are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R 18 , R 19 , R 22 , and R 23 are defined as for formula (IIA);
  • p 1 or 2;
  • R x , R y , and R w are defined as for formula (IA).
  • the invention relates to compounds of formula (VA):
  • R i or R j is —H and the other is represented by the following formula:
  • X 1 and X 2 are each, independently, CH or N;
  • R 12 , R 13 and R 14 are each, independently, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR
  • R 7 , R 8 , R 10 , R 11 , and p are defined as for formula (IIA);
  • R x , R y , and R w are defined as for formula (IA).
  • this invention relates to compounds of formula (VIA):
  • R k or R l is —H and the other is represented by the following formula:
  • the dashed line indicates that the bond is a single bond or a double bond
  • X 3 and X 4 are each, independently, CH, N, CH 2 , NR 16 , O, or S;
  • X 5 and X 6 are each, independently, CR 29 or N;
  • R 15 is H, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR
  • R 16 is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is an alkyl, a cycloalkyl, or an aralkyl;
  • R 29 for each occurrence, is independently, H or a substituent
  • R 7 , R 8 , R 10 , R 11 , R 17 , and p are defined as for formula (IIA);
  • R x , R y , and R w are defined as for formula (IA).
  • the invention relates to compounds of formula (VIIA):
  • R m or R n is —H and the other is represented by the following formula:
  • X 1 and X 2 are each, independently, CH or N;
  • R x , R y , and R w are defined as for formula (IA).
  • the invention relates to compounds of formula (VIIIA):
  • R o or R p is —H and the other is represented by the following formula:
  • X 1 and X 2 are each, independently, CH or N;
  • R x , R y , and R w are defined as for formula (IA).
  • the invention relates to compounds of formula (IXA):
  • R q or R r is —H and the other is represented by the following formula:
  • R 15 and R 19 are defined as for formula (VIA);
  • the invention relates to compounds of formula (XA):
  • R s or R t is —H and the other is represented by the following formula:
  • R 15 , R 16 , and R 29 are defined as for formula (VIA);
  • R x , R y , and R w are defined as for formula (IA).
  • the invention relates to compounds of formula (IB):
  • R 7 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R a or R b is —H and the other is an optionally substituted aryl or an optionally substituted heteroaryl.
  • R 20 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7 , —S
  • R 21 is halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR 7
  • R 7 and R 8 are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R w is defined as for formula (IB).
  • the invention relates to compounds of formula (IVB):
  • R g or R h is —H and the other is:
  • R 10 and R 11 are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R 18 , R 19 , R 20 , R 21 , R 22 , and R 23 are defined as for formula (IIB);
  • R w is defined as for formula (IB).
  • the invention relates to compounds of formula (VB):
  • X 1 and X 2 are each, independently, CH or N;
  • R 12 , R 13 and R 14 are each, independently, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR
  • R w is defined as for formula (IB).
  • R 7 , R 8 , R 10 , R 11 , and p are defined as for formula (IIB).
  • the invention relates to compounds of formula (VIB):
  • R k or R l is —H and the other is represented by the following formula:
  • the dashed line indicates that the bond is a single bond or a double bond
  • X 3 and X 4 are each, independently, CH, N, CH 2 , NR 16 , O, or S;
  • X 5 and X 6 are each, independently, CR 29 or N;
  • R 15 is H, halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 17 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , —SR
  • R 7 , R 8 , R 10 , R 11 , R 17 , and p are defined as for formula (IIB);
  • R 16 is H, an alkyl, a cycloalkyl, an aralkyl, —C(O)R, wherein R is an alkyl, a cycloalkyl, or an aralkyl;
  • R w is defined as for formula (IB).
  • the invention relates to compounds of formula (VIIB):
  • R m or R n is —H and the other is represented by the following formula:
  • X 1 and X 2 are each, independently, CH or N;
  • R w is defined as for formula (IB).
  • the invention relates to compounds of formula (VIIIB):
  • R o or R p is —H and the other is represented by the following formula:
  • X 1 and X 2 are each, independently, CH or N;
  • R w is defined as for formula (IB).
  • R 21 , R 22 , and R 23 are defined as for formula (IIB).
  • the invention relates to compounds of formula (IXB):
  • R q or R r is —H and the other is represented by the following formula:
  • R w is defined as for formula (IB).
  • R 15 and R 19 are defined as for formula (VIB).
  • the invention relates to compounds of formula (XB):
  • R s or R t is —H and the other is represented by the following formula:
  • R w is defined as for formula (IB).
  • R 15 , R 16 , and R 29 are defined as for formula (VIB).
  • one of R a or R b is —H and the other is an optionally substituted phenyl.
  • the phenyl group represented by R a or R b is unsubstituted.
  • the phenyl group represented by R a or R b is substituted with from one to five substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7
  • the phenyl group represented by R a or R b is substituted with from one to five substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the phenyl group represented by R a or R b is substituted with from one to three substituents. More preferably, the phenyl group represented by R a or R b is substituted with three substituents.
  • one of R a or R b is —H and the other is an optionally substituted pyridinyl.
  • the pyridinyl group represented by R a or R b is unsubstituted.
  • the pyridinyl group represented by R a or R b is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7
  • the pyridinyl group represented by R a or R b is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the pyridinyl group represented by R a or R b is substituted with from one to three substituents. More preferably, the pyridinyl group represented by R a or R b is substituted with three substituents.
  • one of R a or R b is —H and the other is an optionally substituted benzo[1,3]dioxolyl.
  • the benzo[1,3]dioxolyl group represented by R a or R b is unsubstituted.
  • the benzo[1,3]dioxolyl group represented by R a or R b is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • substituents independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 )
  • the benzo[1,3]dioxolyl group represented by R a or R b is substituted with from one to three substituents. More preferably, the benzo[1,3]dioxolyl group represented by R a or R b is substituted with one substituent.
  • the 1H-indolyl group represented by R a or R b is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)
  • the 1H-indolyl group represented by R a or R b is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the 1H-indolyl group represented by R a or R b is substituted with from one to three substituents. More preferably, the 1H-indolyl group represented by R a or R b is substituted with one substituent.
  • R c or R d is —H and the other is an optionally substituted pyridinyl.
  • the pyridinyl group represented by-R c or R d is unsubstituted.
  • the pyridinyl group represented by R c or R d is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7
  • the pyridinyl group represented by R c or R d is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the pyridinyl group represented by R c or R d is substituted with from one to three substituents. More preferably, the pyridinyl group represented by R c or R d is substituted with three substituents.
  • R c or R d is —H and the other is an optionally substituted benzo[1,3]dioxolyl.
  • the benzo[1,3]dioxolyl group represented by R c or R d is unsubstituted.
  • the benzo[1,3]dioxolyl group represented by R c or R d is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR
  • the benzo[1,3]dioxolyl group represented by R c or R d is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • substituents independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 )
  • the benzo[1,3]dioxolyl group represented by R c or R d is substituted with from one to three substituents. More preferably, the benzo[1,3]dioxolyl group represented by R c or R d is substituted with one substituent.
  • R c or R d is —H and the other is an optionally substituted 1H-indolyl.
  • the 1H-indolyl group represented by R c or R d is unsubstituted.
  • the 1H-indolyl group represented by R c or R d is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)
  • the 1H-indolyl group represented by R c or R d is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the 1H-indolyl group represented by R c or R d is substituted with from one to three substituents. More preferably, the 1H-indolyl group represented by R c or R d is substituted with one substituent.
  • R e or R f is —H and the other is an optionally substituted phenyl.
  • the phenyl group represented by R e or R f is unsubstituted.
  • the phenyl group represented by R e or R f is substituted with from one to five substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7
  • the phenyl group represented by R e or R f is substituted with from one to five substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the phenyl group represented by R e or R f is substituted with from one to three substituents. More preferably, the phenyl group represented by R e or R f is substituted with three substituents.
  • R e or R f is —H and the other is an optionally substituted pyridinyl.
  • the pyridinyl group represented by R e or R f is unsubstituted.
  • the pyridinyl group represented by R e or R f is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7
  • the pyridinyl group represented by R e or R f is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the pyridinyl group represented by R e or R f is substituted with from one to three substituents. More preferably, the pyridinyl group represented by R e or R f is substituted with three substituents.
  • R e or R f is —H and the other is an optionally substituted benzo[1,3]dioxolyl.
  • the benzo[1,3]dioxolyl group represented by R e or R f is unsubstituted.
  • the benzo[1,3]dioxolyl group represented by R e or R f is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR
  • the benzo[1,3]dioxolyl group represented by R e or R f is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • substituents independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 )
  • the benzo[1,3]dioxolyl group represented by R e or R f is substituted with from one to three substituents. More preferably, the benzo[1,3]dioxolyl group represented by R e or R f is substituted with one substituent.
  • R e or R f is —H and the other is an optionally substituted 1H-indolyl.
  • the 1H-indolyl group represented by R e or R f is unsubstituted.
  • the 1H-indolyl group represented by R e or R f is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)
  • the 1H-indolyl group represented by R e or R f is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the 1H-indolyl group represented by R e or R f is substituted with from one to three substituents. More preferably, the 1H-indolyl group represented by R e or R f is substituted with one substituent.
  • R g or R h is —H and the other is an optionally substituted pyridinyl.
  • the pyridinyl group represented by R g or R h is unsubstituted.
  • the pyridinyl group represented by R g or R h is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7
  • the pyridinyl group represented by R g or R h is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the pyridinyl group represented by R g or R h is substituted with from one to three substituents. More preferably, the pyridinyl group represented by R g or R h is substituted with three substituents.
  • R g or R h is —H and the other is an optionally substituted benzo[1,3]dioxolyl.
  • the benzo[1,3]dioxolyl group represented by R g or R h is unsubstituted.
  • the benzo[1,3]dioxolyl group represented by R g or R h is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR
  • the benzo[1,3]dioxolyl group represented by R g or R h is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • substituents independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 )
  • the benzo[1,3]dioxolyl group represented by R g or R h is substituted with from one to three substituents. More preferably, the benzo[1,3]dioxolyl group represented by R g or R h is substituted with one substituent.
  • the 1H-indolyl group represented by R g or R h is substituted with one or more substituents independently selected from a halo, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, cyano, nitro, guanadino, a haloalkyl, a haloalkoxy, a heteroalkyl, —OR 7 , —NR 10 R 11 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)
  • the 1H-indolyl group represented by R g or R h is substituted with one or more substituents, independently, selected from an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • the 1H-indolyl group represented by R g or R h is substituted with from one to three substituents. More preferably, the 1H-indolyl group represented by R g or R h is substituted with one substituent.
  • R 2 is an optionally substituted phenyl.
  • the phenyl group represented by R 2 is unsubstituted.
  • the phenyl group represented by R 2 is substituted with from one to five groups independently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR 24 , —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkyl amino, dial
  • p is defined as above;
  • R 24 and R 27 are, independently, H, an alkyl, or a cycloalkyl
  • R 25 and R 26 for each occurrence are, independently, H, an alkyl, or a cycloalkyl; or R 25 and R 26 , together with the nitrogen to which they are attached are a heterocyclyl or a heteroaryl; and
  • R 28 for each occurrence, is an alkyl or a cycloalkyl.
  • the phenyl group represented by R 2 is substituted with from one to three substituents. In one aspect of this embodiment, the phenyl group represented by R 2 is substituted with two substituents. In one aspect, the phenyl is substituted with one amino group and one alkoxy group. In one aspect of this embodiment, the phenyl represented by R 2 is substituted with one substituent.
  • R 2 is an optionally substituted pyridinyl. In one aspect of this embodiment, the pyridinyl group represented by R 2 is unsubstituted.
  • the pyridinyl group represented by R 2 is substituted with one or more substituents independently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR 24 , —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkyl amino, dialkylamino, —NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O) p R 28 , —OS(O) p
  • R 2 is an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, an optionally substituted pyridinyl-phenyl, an optionally substituted pyridinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted 1H-indolyl, an optionally substituted oxazolyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, or an optionally substituted benzofuranyl.
  • R 2 is unsubstituted.
  • R 2 is substituted with one or more substituents independently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR 24 , —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkyl amino, dialkylamino, ⁇ NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O)
  • R 4 is an optionally substituted phenyl. In one aspect of this embodiment, the phenyl group represented by R 4 is unsubstituted.
  • the phenyl group represented by R 4 is substituted with from one to five groups independently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR 24 , —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkyl amino, dialkylamino, —NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O) p R 28 , —OS(O) p R 28
  • the phenyl group represented by R 4 is substituted with from one to three substituents. In one aspect of this embodiment, the phenyl group represented by R 4 is substituted with two substituents. In one aspect, the phenyl is substituted with one amino group and one alkoxy group. In one aspect, the phenyl represented by R 4 is substituted with one substituent.
  • R 4 is an optionally substituted pyridinyl. In one aspect of this embodiment, the pyridinyl group represented by R 4 is unsubstituted.
  • the pyridinyl group represented by R 4 is substituted with one or more substituents independently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR 24 , —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkyl amino, dialkylamino, —NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O) p R 28 , —OS(O) p
  • R 4 is an optionally substituted 2,3-dihydro-benzo[1,4]dioxinyl, an optionally substituted biphenyl, an optionally substituted pyridinyl-phenyl, an optionally substituted pyridinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted 1H-indolyl, an optionally substituted oxazolyl, an optionally substituted benzo[1,3]dioxolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, or an optionally substituted benzofuranyl.
  • R 4 is unsubstituted.
  • R 4 is substituted with one or more substituents independently selected from alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, oxazolyl, 1H-tetrazolyl, 1-methyl-1H-tetrazolyl, —OR 24 , —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkyl amino, dialkylamino, —NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O)
  • R 12 , R 13 , and R 14 are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl.
  • R 12 , R 13 , and R 14 are each, independently, an alkoxy.
  • R 12 , R 13 , and R 14 are each methoxy.
  • X 1 and X 2 are CH.
  • X 1 and X 2 are N.
  • X 1 is N and X 2 is CH.
  • X 1 is CH and X 2 is N.
  • X 3 and X 4 are O and X 5 and X 6 are CH.
  • X 3 and X 4 are O; X 5 and X 6 are CH; and R 15 is an alkoxy, such as methoxy.
  • X 3 is CH; X 4 are NR 16 ; and X 5 and X 6 are CH.
  • X 3 is CH; X 4 are NR 16 ; X 5 and X 6 are CH; and R 16 is H.
  • X 3 is CH; X 4 are NR 16 ; X 5 and X 6 are CH; and R 16 is a lower alkyl.
  • R 15 is H, alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkylamino, dialkylamino, —NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O) p R 28 , —OS(O) p OR 27 , —OS(O) p R 28 , —OS(O) p OR 27 , —OS(O) p R 28 , —OS(O) p OR 27 , —
  • R 15 is H, alkoxy, halo, alkyl, haloalkyl, haloalkoxy, nitro, cyano, —SR 24 , —C(O)R 24 , —C(O)OR 24 , —OC(O)R 24 , —C(O)NR 25 R 26 , —NR 24 C(O)R 27 , —NR 24 C(O)OR 27 , —OC(O)NR 25 R 26 , guanidino, amino, alkylamino, dialkylamino, —NR 24 S(O) p R 28 , —S(O) p R 28 , —S(O) p OR 27 , —OS(O) p R 28 , —OS(O) p OR 27 , —OP(O)(OR 27 ) 2
  • R c or R d is —H and the other is a substituted phenyl represented by the following structural formula:
  • R 18 and R 19 are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl; and R 20 is an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, or an alkyl ester; wherein R 7 is defined as above and “ ⁇ ” represents the point of attachment of the
  • R g or R h is —H and the other is a substituted phenyl represented by the following structural formula:
  • R 18 and R 19 are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl; and R 20 is an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, or an alkyl ester; wherein R 7 is defined as above and “ ⁇ ” represents the point of attachment of the
  • R 22 and R 23 are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl; and R 21 is an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, or an
  • R c or R d is —H and the other is a substituted phenyl represented by the following structural formula:
  • R 22 and R 23 are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl; and R 21 is an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, or an alkyl ester, wherein R 7 is defined as above and “ ⁇ ” represents the point of attachment of the
  • R g or R h is —H and the other is a substituted phenyl represented by the following structural formula:
  • R 22 and R 23 are each, independently, an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, an alkyl ester, or hydroxyl; and R 21 is an alkyl, an alkenyl, an alkynyl, cyano, a haloalkyl, an alkoxy, a haloalkoxy, a halo, an amino, an alkylamino, a dialkylamino, —OP(O)(OR 7 ) 2 , —SP(O)(OR 7 ) 2 , nitro, or an alkyl ester, wherein R 7 is defined as above and “ ⁇ ” represents the point of attachment of the
  • R x is R aa , —C(O)YR z , or —C(O)NH—R aa .
  • R x is R aa .
  • R x is C(O)YR z .
  • R aa , R z , and Y are defined as for formula (IA).
  • R x is (R aa ) m . In one aspect, m is 3.
  • R x is R aa and R aa is defined as for formula (IA).
  • R aa is glycine, serine, alanine, phenylalanine, leucine, or methionine.
  • R x is R aa and R aa is a D-amino acid residue or a D-amino acid residue analog.
  • R aa is D-alanine, D-valine, D-leucine, D-isoleucine, D-serine, D-threonine, D-cysteine, D-methionine, D-phenylalanine, D-tyrosine, D-tryptophan, D-aspartic acid, D-asparagine, D-glutamic acid, D-glutamine, D-arginine, D-histidine, D-lysine, or D-proline.
  • R x is R aa and R aa is an L-amino acid residue or an L-amino acid residue analog.
  • R aa is L-alanine, L-valine, L-leucine, L-isoleucine, L-serine, L-threonine, L-cysteine, L-methionine, L-phenylalanine, L-tyrosine, L-tryptophan, L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine, L-arginine, L-histidine, L-lysine, or L-proline.
  • R x is R aa and R y is —H, wherein R aa is defined as for formula (IA).
  • R aa is glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, aspartic acid, asparagine, glutamic acid, glutamine, arginine, histidine, lysine, or proline.
  • R aa is glycine, serine, alanine, phenylalanine, leucine, or methionine.
  • R x is —C(O)YR z and Y and R z are defined as for formula (IA).
  • Y is CH 2 .
  • Y is O.
  • Y is NH.
  • R z is Y 1 and Y 1 is defined as for formula (IA).
  • R z is Alk-NH 2 .
  • R z is Alk-C(O)OH.
  • R z is Het. Alk and Het and defined as for formula (IA).
  • m is 1, 2 or 3.
  • Y 1 is PEG, HPMA copolymer-methacryloyl-Gly-Phe-Leu-Gly-ethylenediamine, or HPMA copolymer-methacryloyl-Gly-Phe-Leu-Gly-OH. In one aspect, Y 1 is PEG.
  • R y is —H.
  • R y is a lower alkyl.
  • Y 1 has a molecular weight greater than 20,000 daltons. In one aspect, Y 1 has a molecular weight of less than 40,000 daltons, but greater than 25,000 daltons.
  • Alk is an optionally substituted lower alkylene.
  • Het is an optionally substituted lower heteroalkyl.
  • X 1 and X 2 are CH and R 12 , R 13 , and R 14 are each methoxy.
  • R x is R aa .
  • R x is (R aa ) m .
  • R x is —R aa —C(O)(CH 2 ) n C(O)OH.
  • R x is —C(O)(CH 2 ) n C(O)OH.
  • R x is —C(O)YR z .
  • R x is —C(O)NH—R aa .
  • R x is —(R aa ) q C(O)(Y 1 ).
  • R aa , Y, R z , Y 1 , m, n, and q are defined as for formula (IA).
  • X 1 and X 2 are CH and R 12 , R 13 , and R 14 are each methoxy.
  • R x is R aa and R w is alkoxy.
  • R x is R aa and R y is —H.
  • R x is R aa , R w is alkoxy, and R y is —H.
  • R x is R aa , R w is alkoxy, and R y is —H.
  • R x is R aa , R w is methoxy, and R y is —H.
  • R aa is defined as for formula (IA).
  • X 1 and X 2 are CH; R 12 , R 13 and R 14 are methoxy; R j is —H; R w is methoxy; R y is —H; and R x is R aa .
  • R aa is defined as for formula (IA).
  • X 1 and X 2 are CH; R 12 , R 13 , and R 14 are each methoxy; and R w is alkoxy. In one aspect, R w is methoxy.
  • R w is alkoxy. In one aspect, R w is methoxy.
  • R a is —H. In some embodiments represented by formula (I), (IA), or (IB), R b is —H. In some embodiments represented by formula (V), (VA), or (VB), R i is —H. In some embodiments represented by formula (V), (VA), or (VB), R j is —H.
  • the invention relates to compounds selected from the group consisting of:
  • the invention relates to compounds selected from the group consisting of:
  • the invention relates to compounds selected from the group consisting of:
  • the invention in another embodiment, relates to pharmaceutical compositions that comprise a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, as an active ingredient, and a pharmaceutically acceptable carrier or vehicle.
  • the compositions are useful for treating or preventing proliferative disorders such as cancer or macular degeneration.
  • the invention in another embodiment, relates to methods for inhibiting tubulin polymerization in a cell comprising contacting the cell with an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • the invention in another embodiment, relates to methods for promoting microtubule depolymerization in a cell comprising contacting the cell with an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • the invention relates to methods for promoting microtubule depolymerization in a subject comprising administering to the subject an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • the invention relates to methods for treating or preventing a proliferative disorder in a subject in need thereof comprising administering an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • the invention relates to methods for treating cancer in a subject in need thereof comprising administering an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • the method involves treating a subject with multidrug resistant cancer.
  • the method involves treating a subject having a solid tumor.
  • the method involves treating a subject having a hematological malignancy.
  • the invention in another embodiment, relates to methods for treating cancer in a subject in need thereof comprising administering an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, and an additional therapeutic agent.
  • the additional therapeutic agent is another anti-cancer agent.
  • the invention in another embodiment, relates to methods for blocking, occluding, or otherwise disrupting blood flow in neovasculature, comprising contacting the neovasculature with an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, and an additional therapeutic agent.
  • the invention in another embodiment, relates to methods blocking, occluding, or otherwise disrupting blood flow in neovasculature in a subject, comprising administering to the subject an effective amount of a compound represented by any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, and an additional therapeutic agent.
  • the compounds of the invention can be made by the methods described herein in Example 1.
  • the compounds of the invention can be prepared using the methods described in Olivera, et al., J. Org. Chem. (2000), 65:6398-6411; Olivera, et al., Tetrahedron (2002), 58:3021-3037; Dominguez, et al., J. Org. Chem. (1996), 61:5435-5439; Olivera, et al., Tet. Let. (1999), 40:3479-3480; Khilya, et al. Ukrainskii Khimicheskii Zhurnal (Russian Edition) (1990), 56(3);280-286.
  • the entire teachings of these references are incorporated herein by reference.
  • the invention provides a method of inhibiting tubulin polymerization in a cell, comprising contacting the cell with an effective amount of a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof, or a pharmaceutical composition comprising a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof.
  • Inhibition of tubulin polymerization can be determined by determining the IC 50 for tubulin polymerization inhibition for a compound as described above, or by using the methods described in Examples 7 and 8, herein.
  • the invention provides a method of treating a proliferative disorder, such as cancer, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof, or a pharmaceutical composition comprising a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof.
  • a proliferative disorder such as cancer
  • Such patients may be treatment naive or may experience partial or no response to conventional therapies.
  • the invention provides a method of blocking, occluding, or otherwise disrupting blood flow in neovasculature, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof, or a pharmaceutical composition comprising a compound of any one of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, and prodrug thereof.
  • Responsiveness to treatment with the compounds of the invention in the case of proliferative disorders can be measured by reduction in the extent or severity of the symptoms associated with the disease or disorder and/or an increase in the longevity and/or quality of life of the subject compared with the absence of the treatment.
  • Responsiveness to treatment with the compounds of the invention in the case of cancer can be measured by a reduction in tumor mass, a reduction in the rate of tumor growth, a reduction in metastasis, a reduction in the severity of the symptoms associated with the cancer and/or an increase in the longevity of the subject compared with the absence of the treatment.
  • the invention also provides methods of preventing, treating, managing, or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof one or more compounds of the invention and one or more other therapies (e.g., one or more prophylactic or therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the prevention, treatment or amelioration of a proliferative disorder, such as cancer, or one or more symptoms associated with said proliferative disorder).
  • therapies e.g., one or more prophylactic or therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the prevention, treatment or amelioration of a proliferative disorder, such as cancer, or one or more symptoms associated with said proliferative disorder.
  • the prophylactic or therapeutic agents of the combination therapies of the invention can be administered sequentially or concurrently.
  • the combination therapies of the invention comprise one or more compounds and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has the same mechanism of action as said compounds (e.g., a therapeutic agent that inhibits tubulin polymerization).
  • the combination therapies of the invention comprise one or more compounds of the invention and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has a different mechanism of action than said compounds.
  • the combination therapies of the present invention improve the prophylactic or therapeutic effect of one or more compounds of the invention by functioning together with the compounds to have an additive or synergistic effect.
  • the combination therapies of the present invention reduce the side effects associated with the therapies (e.g., prophylactic or therapeutic agents).
  • the combination therapies of the present invention reduce the effective dosage of one or more of the therapies.
  • the prophylactic or therapeutic agents of the combination therapies can be administered to a subject, preferably a human subject, in the same pharmaceutical composition.
  • the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions.
  • the prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.
  • a pharmaceutical composition comprising one or more compounds of the invention is administered to a subject, preferably a human, to prevent, treat, manage, or ameliorate a proliferative disorder, such as cancer, or one or more symptoms thereof.
  • a proliferative disorder such as cancer
  • pharmaceutical compositions of the invention may also comprise one or more other agents (e.g., prophylactic or therapeutic agents which are currently being used, have been used, or are known to be useful in the prevention, treatment or amelioration of a proliferative disorder or a symptom thereof).
  • the invention provides methods for preventing, managing, treating or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof in a subject refractory (either completely or partially) to existing agent therapies for such a proliferative disorder, said methods comprising administering to said subject a dose of an effective amount of one or more compounds of the invention and a dose of an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a proliferative disorder or a symptom thereof).
  • a proliferative disorder such as cancer
  • a subject refractory either completely or partially
  • therapies e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a proliferative disorder or a symptom thereof.
  • the invention also provides methods for preventing, treating, managing, or ameliorating a proliferative disorder or a symptom thereof by administering one or more compounds of the invention in combination with any other therapy(ies) to patients who have proven refractory to other therapies but are no longer on these therapies.
  • the compounds of the invention and/or other therapies can be administered to a subject by any route known to one of skill in the art.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
  • Anticancer agents that can be co-administered with the compounds of the invention include TaxolTM, also referred to as “paclitaxel”, which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM, such as TaxotereTM.
  • TaxolTM also referred to as “paclitaxel”
  • TaxotereTM analogs of TaxolTM, such as TaxotereTM.
  • Compounds that have the basic taxane skeleton as a common structure feature have also been shown to have the ability to arrest cells in the G2-M phases due to stabilized microtubules and may be useful for treating cancer in combination with the compounds of the invention.
  • anti-cancer agents that can be employed in combination with the compounds of the invention include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine
  • anti-cancer drugs that can be employed in combination with the compounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP
  • chemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones.
  • alkylating agents useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), ortriazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.
  • alkyl sulfonates e.g., busulfan
  • nitrosoureas e.g., carmustine, lomusitne,
  • antimetabolites useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin
  • Examples of natural products useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunomubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vinblastin, vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunomubicin, doxorubicin, bleomycin
  • enzymes e.g., L-asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents examples include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g.
  • antimetabolites useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).
  • folic acid analog e.g., methotrexate
  • pyrimidine analogs e.g., fluorouracil, floxouridine, Cytarabine
  • purine analogs e.g., mercaptopurine, thioguanine, pentostatin
  • Examples of natural products useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
  • vinca alkaloids e.g., vinblastin, vincristine
  • epipodophyllotoxins e.g., etoposide, teniposide
  • antibiotics e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin
  • enzymes e.g., L-asparagina
  • hormones and antagonists useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • platinum coordination complexes e.g., cisplatin, carboblatin
  • anthracenedione e.g., mitoxantrone
  • substituted urea e.g., hydroxyurea
  • methyl hydrazine derivative e.g., procarbazine
  • adrenocortical suppressant e.g., mitotane, aminoglutethimide
  • anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules and which can be used in combination with the compounds of the invention include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochlor
  • a composition comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof.
  • a composition of the invention comprises one or more prophylactic or therapeutic agents other than a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug thereof.
  • a composition of the invention comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof, and one or more other prophylactic or therapeutic agents.
  • the composition comprises a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • a composition of the invention is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated in such a way that a given pharmaceutical composition or dosage form can be used to treat or prevent proliferative disorders, such as cancer.
  • Preferred pharmaceutical compositions and dosage forms comprise a compound of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable prodrug, salt, solvate, clathrate, hydrate, or prodrug thereof, optionally in combination with one or more additional active agents.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings.
  • a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings.
  • Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
  • transdermal administration to a patient.
  • dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.
  • suspensions e.g., aqueous
  • composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
  • a dosage form suitable for mucosal administration may contain a smaller amount of active ingredient(s) than an oral dosage form used to treat the same indication.
  • This aspect of the invention will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton Pa.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
  • the suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water.
  • Active ingredients that comprise primary or secondary amines e.g., N-desmethylvenlafaxine and N,N-didesmethylvenlafaxine
  • lactose-free means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.
  • Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI).
  • USP U.S. Pharmocopia
  • lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts.
  • Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
  • This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds.
  • water e.g., 5%
  • water is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80.
  • water and heat accelerate the decomposition of some compounds.
  • the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
  • anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as “stabilizer” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups).
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990)18th ed., Mack Publishing, Easton Pa.
  • Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques.
  • Excipients can take a wide variety of forms depending on the form of preparation desired for administration.
  • excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
  • a tablet can be prepared by compression or molding.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient.
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
  • Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof.
  • One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581.
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103J and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • calcium stearate e.g., magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc
  • hydrogenated vegetable oil e.g., peanut oil, cottonseed oil
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • AEROSIL 200 a syloid silica gel
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Plano, Tex.
  • CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.
  • Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
  • Controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the drug In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • a particular extended release formulation of this invention comprises a therapeutically or prophylactically effective amount of a compound of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids which further comprise microcrystalline cellulose and, optionally, hydroxyphopylmethyl-cellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.
  • Such extended release formulations can be prepared according to U.S. Pat. No. 6,274,171, the entirely of which is incorporated herein by reference.
  • a specific controlled-release formulation of this invention comprises from about 6% to about 40% a compound of formulas (I) through (X), (IA) through (XA), (IB) through (XB), or of Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised of ethyl cellulose and hydroxypropylmethylcellulose.
  • Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • water for Injection USP Water for Injection USP
  • aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride
  • Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton Pa. and Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied.
  • excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable.
  • Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton Pa.
  • penetration enhancers can be used to assist in delivering the active ingredients to the tissue.
  • Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
  • the pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied may also be adjusted to improve delivery of one or more active ingredients.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent.
  • Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
  • the amount of the compound or composition of the invention which will be effective in the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each patient depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suitable regiments can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).
  • Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram).
  • the recommended daily dose range of a compound of the invention for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose or preferably as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day.
  • the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response.
  • dosage amounts and dose frequency schedules are also encompassed by the above described dosage amounts and dose frequency schedules.
  • the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
  • the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is 150 ⁇ g/kg, preferably 250 ⁇ g/kg, 500 ⁇ g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight.
  • the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • dosages of prophylactic or therapeutic agents other than compounds of the invention which have been or are currently being used to prevent, treat, manage, or proliferative disorders, such as cancer, or one or more symptoms thereof can be used in the combination therapies of the invention.
  • dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorders, or one or more symptoms thereof, are used in the combination therapies of the invention.
  • the recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof can obtained from any reference in the art including, but not limited to, Hardman et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9 th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57 th Ed., 2003, Medical Economics Co., Inc., Montvale, N.J., which are incorporated herein by reference in its entirety.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • two or more therapies e.
  • one or more compounds of the invention and one or more other the therapies are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g., a third prophylactic or therapeutic agents) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
  • a first therapy e.g., a first prophylactic or therapeutic agents
  • a second therapy e.g., a second prophylactic or therapeutic agents
  • a third therapy e.g., a third prophylactic or therapeutic agents
  • administration of the same compound of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorders, such as cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 ⁇ g/kg, preferably at least 250 ⁇ g/kg, at least 500 ⁇ g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
  • the compounds of the invention may be used as research tools (for example, to evaluate the mechanism of action of new drug agents, to isolate new drug discovery targets using affinity chromatography, as antigens in an ELISA or ELISA-like assay, or as standards in in vitro or in vivo assays).
  • the compounds of this invention inhibit tubulin polymerization and/or target vasculature and, therefore, can be used to inhibit undesirable cellular proliferation in disorders such as cancer.
  • the examples that follow demonstrate these properties.
  • Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA).
  • 1 H-NMR and 13 C-NMR spectra were recorded on a Varian 300 MHz NMR spectrometer. Significant peaks are tabulated in the order: ⁇ (ppm): chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons.
  • 6-Ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g) was dissolved in dry dimethyl formamide (DMF) (5 mL) and treated with iodomethane (Mel) (0.5 mL) and potassium carbonate (1 g) at room temperature for 2 h. The mixture was diluted with water (50 mL) and the precipitate was collected by filtration, washed with water and dried under vacuum to give 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36 g).
  • Tumor cell line MDA-435
  • DMEM medium fetal calf serum
  • IC 50 of the compounds was determined by Five-Parameter Logistic equation. As can be seen from Table 2 several compounds of the invention have IC 50 values comparable to Taxol.
  • the in vitro cytotoxity of the compounds of the invention was determined in the following human cell lines: HL-60 (T-cell leukemia), MDA-435 and MCF-7 (human breast carcinoma). NCl-H460 and H29 (colon carcinoma), DU145 (prostate carcinoma), and MES-S and MES-SA/DX5 (uterine sarcoma).
  • MES-SA is a model of uterine sarcoma, and the cell are sensitive to a number of chemotherapeutic agents including doxorubicin, dactinomycin, mitomycin C, taxol and bleomycin, but resistant to vinblastine and cisplatin.
  • MES-SA/Dx5 was established in the presence of increasing concentrations of doxorubicin.
  • the cells express high levels of mdr-1 mRNA and p-glycoprotein and exhibit cross resistance to more than fifteen chemotherapeutic agents including taxol, etoposide, mitomycin C, colchicine, vinblastine, dactinomycin, 5-fluoroacil, methotrexate and so on. All cells were purchased from ATCC.
  • the cell lines were maintained in RPMI1640 (GIBCO) supplemented with 10% FCS, 100 units/mL penicillin, 100 ug/ml streptomycin, and 2 mM L-glutamine. Cells were split every third day and diluted to a concentration of 2 ⁇ 105 cells/mL one day before the experiment was performed. All experiments were performed on exponentially growing cell cultures. Cell densities were 2.5 ⁇ 10 4 cells/mL in all experiments.
  • Compounds of the invention were prepared by dissolving the compound at a concentration of 10 mM in 100% DMSO. Final concentrations 10, 1, 0.1, 0.01 and 0.001 ⁇ M were obtained by diluting the stock solution directly into the tissue culture medium. Cells were incubated with varying concentrations of compounds for 72 hours and the IC 50 was determined by MTS (i.e. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. IC 50 in this context stands for the concentration of compound required to inhibit 50% tumor cell growth. As can be seen from Tables 3 and 4, compounds of the invention showed much greater activity than Taxol against multidrug resistant cell line MES/DX5.
  • SB cells (2 ⁇ 10 5 cells/mL) were cultured in 12-well plates (2 mL/well) and were left untreated (negative control), treated with Taxol (positive control), or treated with a compound of the invention for 24 h at 37° C. After treatment, the cells were washed one time with 1 ⁇ PBS and stained with FITC labeled anti-Annexin V and PI (10 ⁇ g/ml) for 15 min at room temperature. The cells were analyzed by FACSCalibur (Becton Dickinson). As can be seen from Table 5, many compounds of the invention were more potent apoptosis inducers in SB cells than Taxol.
  • FIGS. 1 and 2 show that the compounds of the invention had similar cytotoxic effects on normal hepatocytes compared to Taxol and had less cytotoxic activity than 17AAG at 1 to 20 uM.
  • MDA-435 cells were cultured in 6-well plates at 1 ⁇ 10 6 cells/well and were untreated (negative control), treated with Taxol (positive control), or treated with a compound of the invention at 37° C. for 20 h. The cells were detached with 1 ⁇ trypsin and washed one time with PBS. Cycle TEST PLUS kit (BD PharMingen, Cat #340242) was used to stain the cells. Cell cycle was analyzed with FACScomp program (BS PharMingen). As can be seen from Table 6, compounds of the invention decrease the percentage of cells entering mitosis (G2/M phase) and increase the apoptotic population compared to untreated cells.
  • Wild-type Chinese Hamster Ovary cells (WT CHO) cells were maintained in Ham's F-12 medium supplemented with 10% fetal bovine serum (FBS; HyClone, Logan, Utah). Cells of low density ( ⁇ 20%) growing on 2-well chambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific) were transfected with a mammalian expression vector encoding ⁇ -tubulin-YFP (Clontech, Palo Alto, Calif.) with the use of FuGENE 6 (Roche MolecularBiochemicals, Indianapolis, Ind.), according to the manufacturer's instructions.
  • FBS fetal bovine serum
  • FBS fetal bovine serum
  • 2-well chambered cover-slips (Labtek (Campbell, Calif.) or Fisher Scientific) were transfected with a mammalian expression vector encoding ⁇ -tubulin-YFP (Clontech, Palo Alto, Calif.) with the use of FuGENE 6 (Roche Molecular
  • the cells were cultured in 400 ⁇ g/ml G418 (Invitrogen, Carlsbad, Calif.)-containing selection medium for 2 weeks. Living cells were examined using a fluorescent microscope for ⁇ -tubulin-YFP expression. Cells in single colonies containing microtubules labeled with ⁇ -tubulin-YFP were lifted and expanded in G418-containing medium.
  • G418 Invitrogen, Carlsbad, Calif.
  • tubulin-YFP expression of ⁇ -tubulin-YFP was confirmed by the presence of the tubulin-YFP labeled microtubule pattern identical to immunostained microtubule pattern of non-transfected cells, as well as by subjecting the cells to Western blot analysis using an anti-GFP antibody (Roche Molecular Biochemicals, Basel, Switzerland) and confirming the correct mass of the ⁇ -tubulin-YFP chimeric protein. Expressed tubulin-YFP was detected as a single band in Western blots.
  • the tubulin-YFP expressing cell lines (referred as CHO- ⁇ -tubulin-YFP cells) were used in the studies described below. Similar methods were used to generate MCF-7 cell lines stably expressing ⁇ -tubulin-YFP (referred as MCF7- ⁇ -tubulin-YFP cells).
  • Tubulin-YFP fluorescence in living cells or fixed cells was captured using a standard filter for FITC and objectives of 20 ⁇ or 60 ⁇ magnification on a Nikon TE300 microscope with a Leica DC50 color digital camera (Leica, Bannockburn, Ill.) or a CoolSnap HQ monochrome CCD camera (Photonetrics, Arlington, Ariz.).
  • the Leica DC50 and CoolSnapHQ cameras were controlled with Leica DC50 software and MetaVue/MetaMorph software, respectively (Universal Imaging Corp, Downingtown, Pa.).
  • Tubulin-YFP signal in live cells is present as typical microtubule network (normal condition, see FIG.
  • FIGS. 5 , 6 and 7 which show MCF7- ⁇ -tubulin-YFP cells treated with 1.0 ⁇ M Compounds 1, 3, and 6 of the invention, respectively).
  • the compounds of the invention inhibit tubulin polymerization.
  • CV-1 cells The effects of compounds of the invention on microtubules were studied in CV-1 cells.
  • the microtubules of CV-1 cells are known to be resistant to the depolymerizing effects of colchicine and vincristine.
  • CV-1 cells were treated with 500 nM of either Compound 3, vincristine, or colchicines, and their microtubules were examined at 24, 48 and 72 hr ( FIGS. 8 , 9 and 10 ). Cells were then fixed and stained to examine microtubule structure. In cells treated with Compound 3 for 24 hrs, no microtubule structure was found ( FIGS. 8B and 8E ). However, disorganized but clear microtubule structures were found in cells treated with either vincristine ( FIG. 8D ) or colchicines ( FIG.
  • the human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, et al., Mol. Pathol. 55:294-299, 2002), was obtained from the American Type Culture Collection (ATCC; Manassas, Va., USA).
  • the human tumor cell line, RERF-LC-AI (RCB0444; S. Kyoizumi, et al., Cancer. Res. 45:3274-3281, 1985), was obtained from the Riken Cell Bank (RCB; Tsukuba, Ibaraki, Japan).
  • the cell lines were cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100 ⁇ L-glutamine, 1% 100 ⁇ Penicillin-Streptomycin, 1% 100 ⁇ sodium pyruvate and 1% 100 ⁇ MEM non-essential amino acids.
  • FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA). Approximately 4-5 ⁇ 10(6) cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37° C. and transferred to a 175 cm 2 tissue culture flask containing 50 ml of growth media and then incubated at 37° C.
  • a 90% confluent flask was washed with 10 mL of room temperature phosphate buffered saline (PBS) and the cells were disassociated by adding 5 mL 1 ⁇ Trypsin-EDTA (Invitrogen) and incubating at 37° C. until the cells detached from the surface of the flask. To inactivate the trypsin, 5 mL of growth media was added and then the contents of the flask were centrifuged to pellet the cells.
  • PBS room temperature phosphate buffered saline
  • the supernatant was aspirated and the cell pellet was resuspended in 10 mL of growth media and the cell number determined using a hemocytometer. Approximately 1-3 ⁇ 10(6) cells per flask were seeded into 175 cm 2 flasks containing 50 mL of growth media and incubated at 37° C. in a 5% CO 2 incubator. When the flasks reached 90% confluence, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice.
  • mice Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Mass., USA). Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 7 and 19 weeks of age at implantation. To implant MDA-MB-435S tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resusupended at a concentration of 50 ⁇ 10(6) cells/mL in PBS.
  • the corpus adiposum is a fat body located in the ventral abdominal vicera in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur).
  • the cells were trypsinized as above, washed in PBS and resuspended at a concentration of 50 ⁇ 10(6) cells/mL in 50% non-supplemented RPMI Media 1640 and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Mass., USA). Using a 27 gauge needle and 1 cc syringe, 0.1 mL of the cell suspension was injected subcutaneously into the flank of nude mice.
  • Tumors were then permitted to develop in vivo until they reached approximately 100-200 mm 3 in volume, which typically required 2-3 weeks following implantation.
  • DMSO dimethyl sulfoxide
  • Stock solutions of test articles were prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared at the start of the study, stored at ⁇ 20° C. and diluted fresh each day for dosing.
  • Cremophore RH40 polyoxyl 40 hydrogenated castor oil
  • D5W 5% dextrose in water
  • Abbott Laboratories North Chicago, Ill., USA
  • DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40.
  • the final formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article (Compound 3 or paclitaxel).
  • Animals were intravenously (i.v.) injected with this solution at 10 ml per kg body weight on a schedule of 3 days per week (Monday, Wednesday, Friday, with no dosing on Saturday and Sunday) for a total of 9-10 doses.
  • the human tumor cell line, MDA-MB435S (ATCC #HTB-129; G. Ellison, et al., Mol. Pathol. 55:294-299, 2002), was obtained and cultured as described in Example 9 above.
  • mice Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Mass., USA). Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 8 and 10 weeks of age at implantation. To implant MDA-MB435S tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resusupended at a concentration of 50 ⁇ 10(6) cells/ml in PBS.
  • the corpus adiposum is a fat body located in the ventral abdominal vicera in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur).
  • D5W Compounds 169 and 174
  • DRD Compound 178
  • solutions of test articles were prepared by dissolving the appropriate amounts of each compound in 5% dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) by sonication in an ultrasonic water bath.
  • stock solutions of test articles were prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath.
  • DMSO dimethyl sulfoxide
  • Cremophore RH40 polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany
  • 5% dextrose in water Abbott Laboratories, North Chicago, Ill., USA
  • This solution was stored at room temperature for up to 3 months prior to use.
  • DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40.
  • the final DRD formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intravenously (i.v.) injected with these formulations at 10 ml per kg body weight on schedules of either 1 day per week for a total of 3 doses, or 3 days per week (Monday, Wednesday, Friday, with no dosing on Saturday and Sunday) for a total of 9 doses.
  • treatment 1 time/week with doses of 2 mg/kg body weight of Compound 169 and 4.55 mg/kg body weight of Compound 174 substantially decreased the growth rate of MDA-MB435S cells in nude mice, with % T/C values of 38 and 25, respectively. This effect was not associated with overt toxicity, as shown by the minimal effect on body weights ( FIG. 16 ).
  • treatment with Compound 178 3 times per week for a total of 3 doses at 25 mg/kg body weight, followed by 3 times per week for a total of 3 doses at 37.5 mg/kg body weight, followed by 3 times per week for a total of 3 doses at 50 mg/kg body weight (arrows) began to show modest efficacy after the dose escalation reached 37.5 mg/kg. This effect was not associated with overt toxicity, as shown by the minimal effect on body weights ( FIG. 18 ).
  • the mouse mammary carcinoma cell line, EMT6 ( ⁇ TCC #CRL-2755), was obtained from the American Type Culture Collection ( ⁇ TCC; Manassas, Va., USA). The cell line was cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100 ⁇ L-glutamine, 1% 100 ⁇ Penicillin-Streptomycin, 1% 100 ⁇ sodium pyruvate and 1% 100 ⁇ MEM non-essential amino acids. FBS was obtained from ⁇ TCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA).
  • PBS room temperature phosphate buffered saline
  • mice Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Mass., USA). Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 8 and 10 weeks of age at implantation. To implant EMT6 tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resusupended at a concentration of 10 ⁇ 10(6) cells/ml in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension was injected subcutaneously into the flank of each nude mouse.
  • a stock solution of the test article were prepared by dissolving an appropriate amount of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath.
  • DMSO dimethyl sulfoxide
  • a solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5% dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) was also prepared by first heating 100% Cremophore RH40 at 50-60° C. until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use.
  • the DMSO stock solution was diluted 1:10 with 20% Cremophore RH40.
  • the final DRD formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article.
  • Tumor-bearing animals were given a single intravenous (i.v.) bolus injections of either DRD vehicle or Compound 3 formulated in DRD, both at 10 mL per kg body weight. Then, 4-24 hr after drug treatment, tumors were excised, cut in half and fixed overnight in 10% neutral-buffered formalin. Each tumor was embedded in paraffin with the cut surfaces placed downwards in the block, and rough cut until a complete section was obtained. From each tumor, 5 ⁇ M serial sections were prepared and stained with hematoxylin and eosin. Slides were evaluated manually using light microscopy with a 10 ⁇ 10 square gridded reticle. The percentage of necrosis in a tumor was quantified at 200 ⁇ magnification by scoring the total number of grid squares containing necrosis and the total number of grid squares containing viable tumor cells.
  • necrotic tissue in the center of EMT6 tumors was observed after a single bolus injection of 25 mg/kg body weight of Compound 3 relative to the baseline necrosis observed in vehicle treated tumors.
  • a near maximal 2.4 fold increase in necrosis was observed 4 hr after drug treatment.
  • vascular targeting mechanism of action such rapid onset of necrosis is consistent with there being a loss of blood flow to tumors resulting in hypoxia and tumor cell death.
  • Compound 249 Depolymerizes Microtubules in CV-1 and Huvec Cells
  • Depolymerizing microtubules not only kills dividing tumor cells but also induces disruption of newly generated blood vessels in tumor.
  • the potency of Compound 249 in depolymerizing microtubules was examined in Africa green monkey kidney fibroblasts (CV1 cells) and primary human umbilical vein endothelium cells (HUVEC cells).
  • the cells were treated with drugs (1, 10, 100, and 1000 nM for CV-1 and 1, 5, 10, 50, 100 nM for HUVEC) for 24 hr and fixed with 3% paraformaldehyde followed by cold methanol treatment to preserve both microtubule structures and depolymerized tubulin in the cytoplasm.
  • the cells were stained with anti-tubulin antibody and subsequently fluorescent conjugated secondary antibody to visualize microtubule networks or cytoplasmic tubulin with fluorescent microscopy.
  • Compound 249 completely depolymerizes MT in a considerable proportion of CV1 cells at 10 nM and HUVEC cells at 1 nM (about 10% for both cell lines; data not shown).
  • At 100 nM for CV1 and 5 nM for HUVEC cells microtubules were completely depolymerized in nearly 100% cells.
  • Tubulin staining in these cells was shown as cytoplasmic location and no microtubule structures were found in those cells.
  • the mouse mammary carcinoma cell line, EMT6 ( ⁇ TCC #CRL-2755), was obtained from the American Type Culture Collection ( ⁇ TCC; Manassas, Va., USA).
  • the cell line was cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100 ⁇ L-glutamine, 1% 100 ⁇ Penicillin-Streptomycin, 1% 100 ⁇ sodium pyruvate and 1% 100 ⁇ MEM non-essential amino acids.
  • FBS was obtained from A TCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, Calif., USA).
  • PBS room temperature phosphate buffered saline
  • mice Seven to eight week old, female Crl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Mass., USA). Animals were housed 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 8 and 10 weeks of age at implantation. To implant EMT6 tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resusupended at a concentration of 10 ⁇ 10 6 cells/mL in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 mL of the cell suspension was injected subcutaneously into the flank of each nude mouse.
  • tumors were permitted to develop in vivo until the majority reached 90-200 mm 3 in tumor volume, which typically required 1 week following implantation.
  • Evans Blue dye assay tumors were permitted to develop in vivo until the majority reached 40-90 mm 3 in tumor volume (to minimize the extent of tumor necrosis), which typically required 4-6 days following implantation. Animals with visibly necrotic, oblong, very small or very large tumors were discarded and only animals carrying tumors that displayed consistent growth rates were selected for use.
  • Compound 174 for dosing, the appropriate amount of compound was dissolved in 5% dextrose in water (D5W; Abbott Laboratories, North Chicago, Ill., USA). Vehicle-treated animals were dosed with D5W.
  • Tumor-bearing animals were given single intravenous (i.v.) bolus injections of either vehicle or Compound 174 at 10 mL per kg body weight. To measure the effect of the drug treatment on tumor growth rates, tumor volumes were measured 3 days after dosing ( FIG. 22 ).
  • tumor-bearing animals were dosed with vehicle or test article at 0 hr, and then i.v. injected with 100 ⁇ L of a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Mo., USA) solution in 0.9% NaCl at +1 hr.
  • Tumors were excised at +4 hr, weighed and the tissue disassociated by incubation in 50 ⁇ L 1 N KOH at 60° C. for 16 hr.
  • 125 ⁇ L of a 0.6 N phosphoric acid and 325 ⁇ L acetone were added, and the samples vigorously vortexed and then microcentrifuged at 3000 RPM for 15 min to pellet cell debris.
  • the optical absorbance of 200 ⁇ L of supernatant was then measured at 620 nM in a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA). Background OD 620 values from similarly sized groups of vehicle or test article-treated animals that had not been injected with dye were subtracted as background. OD 620 values were then normalized for tumor weight and dye uptake was calculated relative to vehicle-treated tumors.
  • the EMT6 mouse mammary carcinoma tumor model in nude mice is highly sensitive to treatment with Compound 174.
  • a single i.v. bolus injection of 4.55 or 3.22 mg/kg body weight of Compound 174 resulted in substantially decreased tumor growth over the subsequent 3 days relative to vehicle-treated animals.
  • Evans Blue dye makes a complex with serum albumin by electrostatic interaction between the sulphonic acid group of the dye and the terminal cationic nitrogens of the lysine residues in albumin. The dye leaves the circulation very slowly, principally by diffusion into extravascular tissues while still bound to albumin. Albumin-dye complex taken up by tumors is located in the extracellular space of non-necrotic tissue, and intracellular uptake and uptake in necrotic regions is negligible.
  • the amount of dye present in a tumor is a measurement of the tumor blood volume and microvessel permeability. As shown in FIG. 23 , a single i.v. bolus injection of 4.55, 3.22 or 2.28 mg/kg body weight of Compound 174 resulted in substantially decreased tumor dye uptake relative to vehicle-treated animals. Such a decrease in dye penetration into the tumor is consistent with there being a loss of blood flow to tumors due to blockage of tumor vasculature, consistent with a vascular disrupting mechanism of action.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
US11/355,922 2005-02-17 2006-02-16 Compounds for the treatment of proliferative disorders Expired - Fee Related US7884094B2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US11/355,922 US7884094B2 (en) 2005-02-17 2006-02-16 Compounds for the treatment of proliferative disorders
US12/883,883 US8269017B2 (en) 2005-02-17 2010-09-16 Compounds for the treatment of proliferative disorders
US13/558,886 US8598366B2 (en) 2005-02-17 2012-07-26 Compounds for the treatment of proliferative disorders
US14/053,845 US9090603B2 (en) 2005-02-17 2013-10-15 Compounds for the treatment of proliferative disorders

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US65389005P 2005-02-17 2005-02-17
US66011205P 2005-03-08 2005-03-08
US73391205P 2005-11-04 2005-11-04
US11/355,922 US7884094B2 (en) 2005-02-17 2006-02-16 Compounds for the treatment of proliferative disorders

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/883,883 Continuation US8269017B2 (en) 2005-02-17 2010-09-16 Compounds for the treatment of proliferative disorders

Publications (2)

Publication Number Publication Date
US20060217389A1 US20060217389A1 (en) 2006-09-28
US7884094B2 true US7884094B2 (en) 2011-02-08

Family

ID=36607371

Family Applications (4)

Application Number Title Priority Date Filing Date
US11/355,922 Expired - Fee Related US7884094B2 (en) 2005-02-17 2006-02-16 Compounds for the treatment of proliferative disorders
US12/883,883 Expired - Fee Related US8269017B2 (en) 2005-02-17 2010-09-16 Compounds for the treatment of proliferative disorders
US13/558,886 Expired - Fee Related US8598366B2 (en) 2005-02-17 2012-07-26 Compounds for the treatment of proliferative disorders
US14/053,845 Expired - Fee Related US9090603B2 (en) 2005-02-17 2013-10-15 Compounds for the treatment of proliferative disorders

Family Applications After (3)

Application Number Title Priority Date Filing Date
US12/883,883 Expired - Fee Related US8269017B2 (en) 2005-02-17 2010-09-16 Compounds for the treatment of proliferative disorders
US13/558,886 Expired - Fee Related US8598366B2 (en) 2005-02-17 2012-07-26 Compounds for the treatment of proliferative disorders
US14/053,845 Expired - Fee Related US9090603B2 (en) 2005-02-17 2013-10-15 Compounds for the treatment of proliferative disorders

Country Status (15)

Country Link
US (4) US7884094B2 (zh)
EP (1) EP1919882A2 (zh)
JP (1) JP5123671B2 (zh)
KR (1) KR101364762B1 (zh)
CN (1) CN101142198B (zh)
AU (1) AU2006214164B2 (zh)
BR (1) BRPI0607688A2 (zh)
CA (1) CA2597430C (zh)
IL (1) IL185016A (zh)
MX (1) MX2007009888A (zh)
NZ (1) NZ560712A (zh)
SG (1) SG164378A1 (zh)
TW (1) TWI385160B (zh)
WO (1) WO2006089177A2 (zh)
ZA (1) ZA200706791B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8598366B2 (en) 2005-02-17 2013-12-03 Synta Pharmaceuticals Corporation Compounds for the treatment of proliferative disorders

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI252847B (en) 2001-07-10 2006-04-11 Synta Pharmaceuticals Corp Synthesis of taxol enhancers
TWI297335B (en) 2001-07-10 2008-06-01 Synta Pharmaceuticals Corp Taxol enhancer compounds
TWI332943B (en) 2001-07-10 2010-11-11 Synta Pharmaceuticals Corp Taxol enhancer compounds
TWI330079B (en) 2003-01-15 2010-09-11 Synta Pharmaceuticals Corp Treatment for cancers
WO2005054209A1 (en) 2003-11-20 2005-06-16 Janssen Pharmaceutica N.V. 7-phenylalkyl substituted 2-quinolinones and 2 quinoxalinones as poly(adp-­ribose) polymerase inhibitors
US7855207B2 (en) 2003-11-20 2010-12-21 Janssen Pharmaceutica, Nv 6-alkenyl and 6-phenylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(adpribose) polymerase inhibitors
RS52999B (en) 2004-06-23 2014-02-28 Synta Pharmaceuticals Corp. BIS (AMIDIDA TIO-HYDRAZIDE) Salts for Cancer Treatment
SG154432A1 (en) 2004-06-30 2009-08-28 Janssen Pharmaceutica Nv Quinazolinedione derivatives as parp inhibitors
EP1771175B1 (en) 2004-06-30 2015-12-23 Janssen Pharmaceutica NV Phthalazine derivatives as parp inhibitors
JP4969443B2 (ja) 2004-06-30 2012-07-04 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Ｐａｒｐ阻害剤としてのキナゾリノン誘導体
US8017654B2 (en) 2005-04-15 2011-09-13 Synta Pharmaceuticals Corp. Combination cancer therapy with bis(thiohydrazide) amide compounds
JP2010501562A (ja) 2006-08-21 2010-01-21 シンタ ファーマシューティカルズ コーポレーション 増殖性障害を治療するための化合物
WO2008027445A2 (en) 2006-08-31 2008-03-06 Synta Pharmaceuticals Corp. Combination with bis(thiohydrazide amides) for treating cancer
US20100093670A1 (en) * 2006-09-14 2010-04-15 Yaming Wu Compounds for the treatment of angiogenesis
ATE542799T1 (de) 2007-03-08 2012-02-15 Janssen Pharmaceutica Nv Chinolinonderivate als parp und tank-inhibitoren
DE102007036685A1 (de) 2007-08-03 2009-02-05 Innora Gmbh Verbesserte arzneimittelbeschichtete Medizinprodukte deren Herstellung und Verwendung
CN101854933A (zh) 2007-09-10 2010-10-06 钙医学公司 调节细胞内钙的化合物
PL2215075T3 (pl) 2007-10-26 2014-04-30 Janssen Pharmaceutica Nv Pochodne chinolinonu jako inhibitory PARP
US8389567B2 (en) 2007-12-12 2013-03-05 Calcimedica, Inc. Compounds that modulate intracellular calcium
ES2367760T3 (es) 2008-03-27 2011-11-08 Janssen Pharmaceutica, N.V. Derivados de quinazolinona como inhibidores de la polimerización de la tubulina.
MX2010010406A (es) 2008-03-27 2010-10-25 Janssen Pharmaceutica Nv Tetrahidrofenantridinonas y tetrahidrociclopentaquinolinonas como inhibidores de la polimerizacion de poli(adp-ribosa)polimerasa-1 y tubulina.
ES2439767T3 (es) * 2008-08-01 2014-01-24 Purdue Pharma Lp Compuestos de tetrahidropiridinilo y dihidropirrolilo y uso de los mismos
WO2010027875A2 (en) 2008-08-27 2010-03-11 Calcimedica Inc. Compounds that modulate intracellular calcium
US8524763B2 (en) 2008-09-22 2013-09-03 Calcimedica, Inc. Inhibitors of store operated calcium release
US8143269B2 (en) 2008-10-03 2012-03-27 Calcimedica, Inc. Inhibitors of store operated calcium release
WO2011015037A1 (en) * 2009-08-05 2011-02-10 The University Of Hongkong Antiviral compounds and methods of making and using there of cross reference to related applications
US8618307B2 (en) 2009-09-16 2013-12-31 Calcimedica, Inc. Compounds that modulate intracellular calcium
US10703722B2 (en) 2010-04-27 2020-07-07 Calcimedica, Inc. Compounds that modulate intracellular calcium
WO2011139765A2 (en) 2010-04-27 2011-11-10 Calcimedica, Inc. Compounds that modulate intracellular calcium
JP6112486B2 (ja) 2010-04-27 2017-04-12 カルシメディカ，インク． 細胞内カルシウムを調節する化合物
WO2012019093A1 (en) * 2010-08-05 2012-02-09 Human Biomolecular Research Institute Synthetic compounds and methods to decrease nicotine self-administration
CN103180316A (zh) 2010-08-27 2013-06-26 钙医学公司 调节细胞内钙的化合物
US8802895B2 (en) 2010-10-18 2014-08-12 Cleveland State University Amide derivatives of benzene-sulfonanilide, pharmaceutical composition thereof and method for cancer treatment using the same
CN102731488A (zh) * 2011-04-02 2012-10-17 中国医学科学院药物研究所 苯并咪唑类衍生物、及其制法和药物组合物与用途
US20120316182A1 (en) 2011-06-10 2012-12-13 Calcimedica, Inc. Compounds that modulate intracellular calcium
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
MX367055B (es) 2012-06-26 2019-08-02 Del Mar Pharmaceuticals El uso de una composición que comprende dianhidrogalactitol, diacetildianhidrogalactitol, y dibromodulcitol, y análogos o derivados de cada uno para el tratamiento de malignidades resistentes a inhibidores de tirosina cinasa.
US9512116B2 (en) 2012-10-12 2016-12-06 Calcimedica, Inc. Compounds that modulate intracellular calcium
US11491154B2 (en) 2013-04-08 2022-11-08 Dennis M. Brown Therapeutic benefit of suboptimally administered chemical compounds
WO2015036463A1 (en) * 2013-09-12 2015-03-19 Merz Pharma Gmbh & Co. Kgaa Topical application of vinca alkaloids for the treatment of actinic keratosis
WO2015057964A2 (en) * 2013-10-16 2015-04-23 The Board Of Regents Of The University Of Texas System Modulation of mrtf-a activity in pathologic fibrosis and wound healing
CN106164060A (zh) * 2014-04-30 2016-11-23 日本电石工业株式会社 环氧乙烷化合物及使用其制造含氮杂环式化合物的方法
CN114712513A (zh) 2015-02-27 2022-07-08 钙医学公司 胰腺炎治疗
US9783519B2 (en) * 2015-06-18 2017-10-10 Hong Kong Baptist University Palladium/silver co-catalyzed tandem reactions synthesis of phenylacetophenone derivatives by oxabenzonorbornadienes with terminal alkynes and their anti-tumor or anti-cancer activities
WO2017027400A1 (en) 2015-08-07 2017-02-16 Calcimedica, Inc. Use of crac channel inhibitors for the treatment of stroke and traumatic brain injury
CN108358864B (zh) * 2017-12-15 2020-07-17 五邑大学 一种2-酰基-5-苯基噁唑类微管蛋白抑制剂的制备方法及应用
CN108707147A (zh) * 2018-06-20 2018-10-26 桑文军 一种新型微管蛋白抑制剂及其在抗肿瘤药物中的应用
CN112979567B (zh) * 2021-03-05 2023-07-18 中国医科大学 Cdk12小分子抑制剂的化合物及其应用

Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4996237A (en) 1987-01-06 1991-02-26 Arizona Board Of Regents Combretastatin A-4
US5430062A (en) 1992-05-21 1995-07-04 Research Corporation Technologies, Inc. Stilbene derivatives as anticancer agents
US5561122A (en) 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
US5569786A (en) 1987-01-06 1996-10-29 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated "combretastatins"
WO1997014679A2 (en) 1995-10-17 1997-04-24 G.D. Searle & Co. Method of detecting cyclooxygenase-2
US5663053A (en) 1992-02-11 1997-09-02 Smithkline Beecham Corporation Inhibition of inflammatory lipid mediators
US5674906A (en) 1995-03-07 1997-10-07 Ajinomoto Co., Inc. Stilbene compounds and pharmaceutical compositions containing them
US5731353A (en) 1993-09-08 1998-03-24 Ajinomoto Co., Inc. Stilbene derivatives and pharmaceutical compositions containing them
WO1998016227A1 (en) 1996-10-15 1998-04-23 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
US5859035A (en) 1996-04-03 1999-01-12 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
WO1999002507A1 (fr) 1997-07-09 1999-01-21 Nippon Soda Co., Ltd. Composes d'isoxazole, procede de preparation desdits composes, ainsi qu'insecticides et acaricides
US5886015A (en) 1997-06-02 1999-03-23 Rohm And Haas Company Benzyloxy substituted aromatics and their use as fungicides and insecticides
US5972986A (en) 1997-10-14 1999-10-26 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
WO2000015229A1 (en) 1998-09-17 2000-03-23 Bristol-Myers Squibb Company METHOD FOR TREATING DIABETES EMPLOYING AN aP2 INHIBITOR AND COMBINATION
JP2000086657A (ja) 1998-09-10 2000-03-28 Teikoku Hormone Mfg Co Ltd ５−アミノイソキサゾール誘導体
US6136839A (en) 1995-06-12 2000-10-24 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
WO2002000651A2 (en) 2000-06-27 2002-01-03 Bristol-Myers Squibb Pharma Company Factor xa inhibitors
US6342510B1 (en) 1995-06-12 2002-01-29 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist
WO2002022610A1 (en) 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Isoxazoles and their use as inhibitors of erk
US6462087B1 (en) 1998-04-03 2002-10-08 Ajinomoto Co., Inc. Anti-tumor composition
US6525059B1 (en) 1998-11-20 2003-02-25 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6538038B1 (en) 1999-02-18 2003-03-25 Oxigene, Inc. Compositions and methods for use in targeting vascular destruction
WO2003031404A2 (en) 2001-10-12 2003-04-17 Onconova Therapeutics, Inc. Processes for the preparation of substituted isoxazoles and 2-isoxazolines
US20030105141A1 (en) 2001-04-17 2003-06-05 Ping Gao Finely self-emulsifiable pharmaceutical composition
US6593374B2 (en) 2000-03-10 2003-07-15 Baylor University Tubulin binding ligands and corresponding prodrug constructs
WO2003062392A2 (en) 2002-01-18 2003-07-31 Ceretek Llc Methods of treating conditions associated with an edg receptor
EP1336602A1 (en) 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
WO2004022032A2 (en) 2002-07-31 2004-03-18 Pharmacia Corporation Pharmaceutical dosage form comprising a sulfite compound
WO2004026865A1 (en) 2002-09-18 2004-04-01 Pfizer Products Inc. Novel isothiazole and isoxazole compounds as transforming growth factor (tgf) inhibitors
WO2004072051A1 (en) 2003-02-11 2004-08-26 Vernalis (Cambridge) Limited Isoxazole compounds as inhibitors of heat shock proteins
WO2004087153A2 (en) 2003-03-28 2004-10-14 Chiron Corporation Use of organic compounds for immunopotentiation
WO2004099159A1 (en) 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Substituted heteroaryls as inhibitors of protein tyrosine phosphatases
WO2004110351A2 (en) 2003-05-14 2004-12-23 Anadys Pharmaceuticals, Inc. Heterocyclic compounds for treating hepatitis c virus
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
WO2005000300A1 (en) 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
WO2005007635A2 (en) 2003-07-18 2005-01-27 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Combretastatin derivatives with cytotoxic action
US6849656B1 (en) 1999-09-17 2005-02-01 Baylor University Indole-containing and combretastatin-related anti-mitotic and anti-tubulin polymerization agents
WO2005028475A2 (en) 2003-09-04 2005-03-31 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
WO2005044194A2 (en) 2003-10-28 2005-05-19 Pharmacia Corporation TREATMENT OR PREVENTION OF NEOPLASIA BY USE OF AN Hsp90 INHIBITOR
US20050131036A1 (en) 2003-12-11 2005-06-16 Byoung-Mog Kwon Pharmaceutical compositions of diaryl-isoxazole derivatives for the prevention and treatment of cancers
WO2005066162A1 (en) 2003-12-23 2005-07-21 Human Biomolecular Research Institute Synthetic compounds and derivatives as modulators of smoking or nicotine ingestion and lung cancer
US20050169881A1 (en) 2002-04-11 2005-08-04 Ronit Satchi-Fainaro Tnp-470 polymer conjugates and use thereof
WO2006092059A1 (en) 2005-03-04 2006-09-08 Fan Wu Design and synthesis of novel antimicrobials
WO2006124687A1 (en) 2005-05-12 2006-11-23 University Of Medicine And Dentistry Of New Jersey Opioid receptor subtype-selective agents

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020169881A1 (en) * 2001-05-10 2002-11-14 International Business Machines Corporation Method and apparatus for distributed access to services in a network data processing system
NZ560712A (en) 2005-02-17 2010-12-24 Synta Pharmaceuticals Corp (3,4,5-trisubstituted-phenyl)isoxazole combretastin derivatives for the treatment of disorders

Patent Citations (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5569786A (en) 1987-01-06 1996-10-29 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated "combretastatins"
US4996237A (en) 1987-01-06 1991-02-26 Arizona Board Of Regents Combretastatin A-4
US5663053A (en) 1992-02-11 1997-09-02 Smithkline Beecham Corporation Inhibition of inflammatory lipid mediators
US5430062A (en) 1992-05-21 1995-07-04 Research Corporation Technologies, Inc. Stilbene derivatives as anticancer agents
US5731353A (en) 1993-09-08 1998-03-24 Ajinomoto Co., Inc. Stilbene derivatives and pharmaceutical compositions containing them
US5561122A (en) 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
US5674906A (en) 1995-03-07 1997-10-07 Ajinomoto Co., Inc. Stilbene compounds and pharmaceutical compositions containing them
US6136839A (en) 1995-06-12 2000-10-24 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
US6342510B1 (en) 1995-06-12 2002-01-29 G. D. Searle & Co. Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist
WO1997014679A2 (en) 1995-10-17 1997-04-24 G.D. Searle & Co. Method of detecting cyclooxygenase-2
US5859035A (en) 1996-04-03 1999-01-12 Merck & Co., Inc. Arylheteroaryl inhibitors of farnesyl-protein transferase
WO1998016227A1 (en) 1996-10-15 1998-04-23 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
US5886015A (en) 1997-06-02 1999-03-23 Rohm And Haas Company Benzyloxy substituted aromatics and their use as fungicides and insecticides
WO1999002507A1 (fr) 1997-07-09 1999-01-21 Nippon Soda Co., Ltd. Composes d'isoxazole, procede de preparation desdits composes, ainsi qu'insecticides et acaricides
US6469040B2 (en) 1997-10-14 2002-10-22 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
US20030220384A1 (en) 1997-10-14 2003-11-27 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
US5972986A (en) 1997-10-14 1999-10-26 G.D. Searle & Co. Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
US6462087B1 (en) 1998-04-03 2002-10-08 Ajinomoto Co., Inc. Anti-tumor composition
JP2000086657A (ja) 1998-09-10 2000-03-28 Teikoku Hormone Mfg Co Ltd ５−アミノイソキサゾール誘導体
WO2000015229A1 (en) 1998-09-17 2000-03-23 Bristol-Myers Squibb Company METHOD FOR TREATING DIABETES EMPLOYING AN aP2 INHIBITOR AND COMBINATION
WO2000015230A1 (en) 1998-09-17 2000-03-23 Bristol-Myers Squibb Company METHOD FOR TREATING ATHEROSCLEROSIS EMPLOYING AN aP2 INHIBITOR AND COMBINATION
US6525059B1 (en) 1998-11-20 2003-02-25 G. D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
US6538038B1 (en) 1999-02-18 2003-03-25 Oxigene, Inc. Compositions and methods for use in targeting vascular destruction
US6849656B1 (en) 1999-09-17 2005-02-01 Baylor University Indole-containing and combretastatin-related anti-mitotic and anti-tubulin polymerization agents
US6593374B2 (en) 2000-03-10 2003-07-15 Baylor University Tubulin binding ligands and corresponding prodrug constructs
WO2002000651A2 (en) 2000-06-27 2002-01-03 Bristol-Myers Squibb Pharma Company Factor xa inhibitors
WO2002022610A1 (en) 2000-09-15 2002-03-21 Vertex Pharmaceuticals Incorporated Isoxazoles and their use as inhibitors of erk
US6649640B2 (en) 2000-09-15 2003-11-18 Vertex Pharmaceuticals Incorporated Isoxazole compositions useful as inhibitors of ERK
US20030105141A1 (en) 2001-04-17 2003-06-05 Ping Gao Finely self-emulsifiable pharmaceutical composition
WO2003031404A2 (en) 2001-10-12 2003-04-17 Onconova Therapeutics, Inc. Processes for the preparation of substituted isoxazoles and 2-isoxazolines
WO2003062392A2 (en) 2002-01-18 2003-07-31 Ceretek Llc Methods of treating conditions associated with an edg receptor
EP1336602A1 (en) 2002-02-13 2003-08-20 Giovanni Scaramuzzino Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases
US20050169881A1 (en) 2002-04-11 2005-08-04 Ronit Satchi-Fainaro Tnp-470 polymer conjugates and use thereof
WO2004022032A2 (en) 2002-07-31 2004-03-18 Pharmacia Corporation Pharmaceutical dosage form comprising a sulfite compound
WO2004026865A1 (en) 2002-09-18 2004-04-01 Pfizer Products Inc. Novel isothiazole and isoxazole compounds as transforming growth factor (tgf) inhibitors
WO2004072051A1 (en) 2003-02-11 2004-08-26 Vernalis (Cambridge) Limited Isoxazole compounds as inhibitors of heat shock proteins
WO2004087153A2 (en) 2003-03-28 2004-10-14 Chiron Corporation Use of organic compounds for immunopotentiation
WO2004099159A1 (en) 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Substituted heteroaryls as inhibitors of protein tyrosine phosphatases
WO2004110351A2 (en) 2003-05-14 2004-12-23 Anadys Pharmaceuticals, Inc. Heterocyclic compounds for treating hepatitis c virus
WO2005000300A1 (en) 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
WO2005000309A2 (en) 2003-06-27 2005-01-06 Ionix Pharmaceuticals Limited Chemical compounds
WO2005007635A2 (en) 2003-07-18 2005-01-27 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Combretastatin derivatives with cytotoxic action
WO2005028475A2 (en) 2003-09-04 2005-03-31 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
WO2005044194A2 (en) 2003-10-28 2005-05-19 Pharmacia Corporation TREATMENT OR PREVENTION OF NEOPLASIA BY USE OF AN Hsp90 INHIBITOR
US20050131036A1 (en) 2003-12-11 2005-06-16 Byoung-Mog Kwon Pharmaceutical compositions of diaryl-isoxazole derivatives for the prevention and treatment of cancers
WO2005066162A1 (en) 2003-12-23 2005-07-21 Human Biomolecular Research Institute Synthetic compounds and derivatives as modulators of smoking or nicotine ingestion and lung cancer
WO2006092059A1 (en) 2005-03-04 2006-09-08 Fan Wu Design and synthesis of novel antimicrobials
WO2006124687A1 (en) 2005-05-12 2006-11-23 University Of Medicine And Dentistry Of New Jersey Opioid receptor subtype-selective agents

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Dominguez, E., et al., "A Convenient On-Pot Preparative Method for 4,5-Diarylisoxazoles" J. of Organic Chem. 61(16), 5435-5439 (1996).
Gourdeau, H., et al., "Antivascular and Antitumor Evaluation of 2-amino-4-(3-bromo-4, 5-dimethyoxy-phenyl)-3-cyano-4H-chromenes, A Novel Series of Anticancer Agents" Mol. Cancer Ther. 3(11), 1375-1383 (2004).
Khilya, V.P., et al., "Reaction of Isoflavones and Their 4-thioxo Analogs with Hydroxylamine" Ukrainskii Khimicheskii Zhurnal (Russian Ed.) 56(3), 280-6 (1990).
Kirwan, I., et al., "Comparative Preclinical Pharmacokinetic and Metabolic Studies of the Combretastatin Prodrugs Combretastatin A4 Phosphate and A1 Phosphate" Clinical Cancer Research, 10, 1446-1453 (2004).
Maya, Ana B. S., et al., "Further Naphthylcombretastatins. An Investigation on the Role of the Naphthalene Moiety," J. Med. Chem. 48:556-568 (2005).
Maya, Ana B.S., et al., "New Naphthylcombretastatins. Modifications on the Ethylene Bridge," Bioorganic & Medicinal Chemistry 13:2097-2107 (2005).
Medarde, Manuel and Maya, Ana B., "Naphthalene Combretastain Analogues: Synthesis, Cytotoxicity and Antitubulin Activity" J. Enzyme Inhib. Med. Chem., 19(6), 521-540 (2004).
Ohsumi, K., et al., "Synthesis and Antitumor Activity of Cis-Restricted Combretastatins: 5-Membered Heterocyclic Analogues" Bioorg. Med. Chem. Lett., 8, 3153-3158 (1998).
Olivera, R., et al., "A Convenient Strategy for the Synthesis of 4,5-bis(o-haloaryl) isoxazoles" J. of Organic Chem. 65(20), 6398-6411 (2000).
Olivera, R., et al., "Phenyliodine (III) bis(trifluoroacetate) Mediated Synthesis of Phenantrho [9,10-d] Fused Isoxazoles and Pyrimidines" Tetrahedron Letters 40(17), 3479-3480 (1999).
Olivera, R., et al., "The Amine Exchange/Biaryl Coupling Sequence: A Direct Entry to the Phenanthro [9,10-d] Heterocyclic Framework" Tetrahedron 58(15), 3021-3037 (2002).
Sanmartin, R., et al., "Crystal Structure of 4-phenyl-5-(2,3,4-trimethyoxyphenyl) isoxazole" Crystal Research and Tech. 32(7), 1015-1020 (1997).
Shin, K.D., et al., "Blocking Tumor Cell Migration and Invasion with Biphenyl Isoxazole Derivative KRIBB3, A Synthetic Molecule That Inhibits Hsp27 Phosphorylation," The Journal of Biological Chemistry, 280(50):41439-41448 (2005).
Simoni, D., et al., "Heterocyclic and Phenyl Double-Bond Locked Combretastatin Analogues Possessing Potent Apoptosis-Inducing Activity in HL60 and in MDR Cell Lines" J. Med. Chem. 48, 723-736 (2005).
Wang, L., et al., "Potent, Orally Active Heterocycle-Based Combretastatin A-4 Analogues: Synthesis, Structure-Activity Relationship, Pharmacokinetics, and In Vivo Antitumor Activity Evaluation" J. Med. Chem., 45, 1697-1711 (2002).

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8598366B2 (en) 2005-02-17 2013-12-03 Synta Pharmaceuticals Corporation Compounds for the treatment of proliferative disorders
US9090603B2 (en) 2005-02-17 2015-07-28 Synta Pharmaceuticals Corporation Compounds for the treatment of proliferative disorders

Also Published As

Publication number Publication date
IL185016A0 (en) 2007-12-03
AU2006214164A1 (en) 2006-08-24
TW200640883A (en) 2006-12-01
US8598366B2 (en) 2013-12-03
US9090603B2 (en) 2015-07-28
SG164378A1 (en) 2010-09-29
EP1919882A2 (en) 2008-05-14
AU2006214164B2 (en) 2010-12-09
US8269017B2 (en) 2012-09-18
US20110059893A1 (en) 2011-03-10
US20060217389A1 (en) 2006-09-28
KR101364762B1 (ko) 2014-02-17
NZ560712A (en) 2010-12-24
KR20070107131A (ko) 2007-11-06
ZA200706791B (en) 2012-01-25
CN101142198A (zh) 2008-03-12
JP5123671B2 (ja) 2013-01-23
MX2007009888A (es) 2007-10-16
US20140045795A1 (en) 2014-02-13
TWI385160B (zh) 2013-02-11
US20120289483A1 (en) 2012-11-15
CA2597430A1 (en) 2006-08-24
WO2006089177A2 (en) 2006-08-24
WO2006089177A3 (en) 2006-12-14
JP2008530240A (ja) 2008-08-07
CN101142198B (zh) 2012-10-31
IL185016A (en) 2014-08-31
BRPI0607688A2 (pt) 2009-09-22
CA2597430C (en) 2014-08-05

Similar Documents

Publication Publication Date Title
US9090603B2 (en) Compounds for the treatment of proliferative disorders
US9175022B2 (en) Compounds for the treatment of proliferative disorders
US8188075B2 (en) Triazole compounds that modulate HSP90 activity
US20100093670A1 (en) Compounds for the treatment of angiogenesis
US8399435B2 (en) Compounds for the treatment of proliferative disorders

Legal Events

Date Code Title Description
AS Assignment

Owner name: SYNTA PHARMACEUTICALS CORP., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUN, LIJUN;BORELLA, CHRISTOPHER;LI, HAO;AND OTHERS;SIGNING DATES FROM 20060418 TO 20060425;REEL/FRAME:017733/0015

Owner name: SYNTA PHARMACEUTICALS CORP., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SUN, LIJUN;BORELLA, CHRISTOPHER;LI, HAO;AND OTHERS;REEL/FRAME:017733/0015;SIGNING DATES FROM 20060418 TO 20060425

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552)

Year of fee payment: 8

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20230208